Depressed natural killer cell activity due to decreased natural killer cell population in a vitamin E-deficient patient with Shwachman syndrome: reversible natural killer cell abnormality by alpha-tocopherol supplementation

Adachi N; Migita M; Ohta T; Higashi A; Matsuda I Department of Paediatrics, Kumamoto University School of Medicine, Japan.

Eur J Pediatr (Germany) Jun 1997, 156 (6) p444-8

Natural Killer ( NK ) cell activity was examined in a 16-month-old Japanese boy with Shwachman syndrome associated with severe vitamin E deficiency. As evaluated by 51Cr-release assay from K562 cells, NK cell activity was constantly decreased. After 8 weeks of oral alpha-tocopherol (alpha-Toc) supplementation (100 mg/day), NK cell activity had normalised. When alpha-Toc supplementation was interrupted for 16 weeks. NK cell activity again decreased. Flow cytometry of peripheral lymphocytes revealed a lowered number of CD16+ CD 56- fraction, which has the most potent NK cell activity . Single cell-in-agarose assay, to investigate the binding and cytolytic activity of NK cell at the single cell level, revealed that the number of NK cells which bind to K562 cell was decreased, but that the cytolytic activity of the individual binding cell was relatively unaffected. A second supplementation of alpha-Toc for 8 weeks successfully restored NK cell activity, the number of cells expressing NK cell markers and the number of K562-binding cells as compared to the age-matched normal range. CONCLUSION: These results indicate that severe vitamin E deficiency caused impaired NK cell activity due to a decrease in the number of CD16+ CD56- NK cells and that this abnormality is reversible with alpha-Toc supplementation.

Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HN019).

Arunachalam K, Gill HS, Chandra RK. Memorial University of Newfoundland, Janeway Child Health Centre, St Johns, Newfoundland, Canada.

Eur J Clin Nutr 2000 Mar;54(3):263-7

OBJECTIVE: To determine the effects of dietary consumption of Bifidobacterium lactis (strain HN019, DR10TM) on natural immunity. DESIGN: A randomized, double blind, placebo-controlled clinical trial. SETTING: Janeway Medical Centre, Memorial University, St Johns, Newfoundland. SUBJECTS: Twenty-five healthy elderly volunteers (median age 69 y; range 60-83 y). INTERVENTIONS: Twelve control subjects consumed 180 ml low-fat/low-lactose milk twice daily for a period of 6 weeks; 13 test subjects consumed milk supplemented with 1.5x1011 colony-forming units of B. lactis twice daily. Indices of natural immunity, including interferon production, phagocytic capacity and phagocyte-mediated bactericidal activity, were determined via peripheral blood at 0, 3, 6 and 12 weeks post-trial commencement. RESULTS: Subjects who consumed milk containing B. lactis for 6 weeks produced significantly enhanced levels of interferon-alpha, upon stimulation of their peripheral blood mononuclear cells in culture, in comparison to the placebo control group who received milk alone. There were also significant increases in polymorphonuclear cell phagocytic capacity among test group subjects, following consumption of milk supplemented with B. lactis, while individuals who consumed B. lactis-supplemented milk or milk alone showed enhanced phagocyte-mediated bactericidal activity. CONCLUSIONS: The results demonstrate that dietary consumption of B. lactis HN019 can enhance natural immunity in healthy elderly subjects, and that a relatively short-term dietary regime (6 weeks) is sufficient to impart measurable improvements in immunity that may offer significant health benefits to consumers. SPONSORS: Financial support for this project was provided by the New Zealand Dairy Board.

Recent progress in treatment and secondary prevention of breast cancer with supplements.

Austin, S.

Altern. Med. Rev. 1997; 2(1): 4-11.

No abstract available.

Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice.

Bagchi D, Garg A, Krohn RL, Bagchi M, Bagchi DJ, Balmoori J, Stohs SJ. Creighton University School of Pharmacy, Omaha, Nebraska, USA.

Gen Pharmacol 1998 May;30(5):771-6

1. The comparative protective abilities of a grape seed proanthocyanidin extract (GSPE) (25-100 mg/kg), vitamin C (100 mg/kg), vitamin E succinate (VES) (100 mg/kg) and beta-carotene (50 mg/kg) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced lipid peroxidation and DNA fragmentation in the hepatic and brain tissues, as well as production of reactive oxygen species by peritoneal macrophages, were assessed. 2. Treatment of mice with GSPE (100 mg/kg), vitamin C, VES and beta-carotene decreased TPA-induced production of reactive oxygen species, as evidenced by decreases in the chemiluminescence response in peritoneal macrophages by approximately 70%, 18%, 47% and 16%, respectively, and cytochrome c reduction by approximately 65%, 15%, 37% and 19%, respectively, compared with controls. 3. GSPE, vitamin C, VES and beta-carotene decreased TPA-induced DNA fragmentation by approximately 47%, 10%, 30% and 11%, respectively, in the hepatic tissues, and 50%, 14%, 31% and 11%, respectively, in the brain tissues, at the doses that were used. Similar results were observed with respect to lipid peroxidation in hepatic mitochondria and microsomes and in brain homogenates. 4. GSPE exhibited a dose-dependent inhibition of TPA-induced lipid peroxidation and DNA fragmentation in liver and brain, as well as a dose-dependent inhibition of TPA-induced reactive oxygen species production in peritoneal macrophages. 5. GSPE and other antioxidants provided significant protection against TPA-induced oxidative damage, with GSPE providing better protection than did other antioxidants at the doses that were employed.

Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro.

Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ. School of Pharmacy, Creighton University, Omaha, NE 68178, USA.

Res Commun Mol Pathol Pharmacol 1997 Feb;95(2):179-89

Proanthocyanidins, a group of polyphenolic bioflavonoids, have been reported to exhibit a wide range of biological, pharmacological and chemoprotective properties against oxygen free radicals. We have assessed the concentration-dependent oxygen free radical scavenging abilities of a grape seed proanthocyanidin extract (GSPE), vitamin C and vitamin E succinate (VES) as well as superoxide dismutase, catalase and mannitol against biochemically generated superoxide anion and hydroxyl radical using a chemiluminescence assay and cytochrome c reduction. A concentration-dependent inhibition was demonstrated by GSPE. At a 100 mg/l concentration, GSPE exhibited 78-81% inhibition of superoxide anion and hydroxyl radical. Under similar conditions, vitamin C inhibited these two oxygen free radicals by approximately 12-19%, while VES inhibited the two radicals by 36-44%. The combination of superoxide dismutase and catalase inhibited superoxide anion by approximately 83%, while mannitol resulted in an 87% inhibition of hydroxyl radical. The results demonstrate that GSPE is a more potent scavenger of oxygen free radicals as compared to vitamin C and VES.

Nutrition in pediatric HIV infection: setting the research agenda. Nutrition and immune function: overview.

Beisel WR. Department of Immunology and Infectious Diseases, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD, USA.

J Nutr. 1996 Oct;126(10 Suppl):2611S-2615S.

Malnutrition can have adverse, even devastating effects on the antigen-specific arms of the immune system and on generalized host defensive mechanisms. Protein/energy malnutrition and/or deficiencies of single nutrients that assist in nucleic acid metabolism generally lead to atrophy of lymphoid tissues and dysfunctions of cell-mediated immunity. Deficiencies of single nutrients can impair production of key proteins. Trace element deficiencies are often multifactorial. Essential fatty acid deficiencies can reduce or perturb the synthesis of cytokine-induced eicosanoids. Arginine deficiency can diminish the production of nitric oxide, and deficiencies of antioxidant nutrients can allow increases in the damaging effects of free oxygen radicals. Humoral immunity continues to be maintained, although new primary responses to T-cell-dependent antigens are generally subnormal in both magnitude and quality. Immunological dysfunctions associated with malnutrition have been termed Nutritionally Acquired Immune Deficiency Syndromes (NAIDS). Infants and small children are at great risk because they possess only immature, inexperienced immune systems and very small protein reserves. The combination of NAIDS and common childhood infections is the leading cause of human mortality. NAIDS can generally be corrected by appropriate nutritional rehabilitation, but from a viewpoint highly important to this Workshop, AIDS and NAIDS are intensely synergistic. AIDS-induced malnutrition can lead to the secondary development of NAIDS, with its much broader array of additional immunological dysfunctions. The complex and far reaching insults to the immune system caused by NAIDS, and the synergistic combination of NAIDS and AIDS, thereby hasten the demise of many victims of AIDS. Aggressive nutritional support for children with HIV infections could delay, or lessen, the development of NAIDS and avoidance of NAIDS would improve both quality and length of life.

Whey proteins as a food supplement in HIV-seropositive individuals.

Bounous G, Baruchel S, Falutz J, Gold P. Department of Surgery, Montreal General Hospital, Quebec.

Clin Invest Med. 1993 Jun;16(3):204-9.

On the basis of numerous animal experiments, a pilot study was undertaken to evaluate the effect of undenatured, biologically active, dietary whey protein in 3 HIV-seropositive individuals over a period of 3 months. Whey protein concentrate was prepared so that the most thermosensitive proteins, such as serum albumin which contains 6 glutamylcysteine groups, would be in undenatured form. Whey protein powder dissolved in a drink of the patient's choice was drunk cold in quantities that were increased progressively from 8.4 to 39.2 g per day. Patients took whey proteins without adverse side effects. In the 3 patients whose body weight had been stable in the preceding 2 months, weight gain increased progressively between 2 and 7 kg, with 2 of the patients reaching ideal body weight. Serum proteins, including albumin, remained unchanged and within normal range, indicating that protein replenishment per se was not likely the cause of increased body weight. The glutathione content of the blood mononuclear cells was, as expected, below normal values in all patients at the beginning of the study. Over the 3-month period, glutathione levels increased in all 3 cases. In conclusion, these preliminary data indicate that, in patients who maintain an adequate total caloric intake, the addition of "bioactive" whey protein concentrate as a significant portion of total protein intake increases body weight and shows elevation of glutathione (GSH) content of mononuclear cells toward normal levels. This pilot study will serve as a basis for a much larger clinical trial.

Cover Story: Lactoferrin: the bioactive peptide that fights disease.

Brink, W.

Life Extension Magazine 2000 Oct; 6(10): 20-6. Ft. Lauderdale, FL: Life Extension Foundation.

http://www.lef.org/magazine/mag2000/oct2000_report_lactoferrin.html

In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients.

Broumand N; Sahl L; Tilles JG; See DM Department of Medicine, U.C. Irvine Medical Center, Orange 92668, USA.

Immunopharmacology (Netherlands) Jan 1997, 35 (3) p229-35

Extracts of Echinacea purpurea and Panax ginseng were evaluated for their capacity to stimulate cellular immune function by peripheral blood mononuclear cells (PBMC) from normal individuals and patients with either the chronic fatigue syndrome or the acquired immunodeficiency syndrome. PBMC isolated on a Ficoll-hypaque density gradient were tested in the presence or absence of varying concentrations of each extract for natural killer ( NK ) cell activity versus K562 cells and antibody-dependent cellular cytotoxicity (ADCC) against human herpesvirus 6 infected H9 cells. Both echinacea and ginseng, at concentrations > or = 0.1 or 10 micrograms/kg, respectively, significantly enhanced NK-function of all groups. Similarly, the addition of either herb significantly increased ADCC of PBMC from all subject groups. Thus, extracts of Echinacea purpurea and Panax ginseng enhance cellular immune function of PBMC both from normal individuals and patients with depressed cellular immunity.

Prospects of the clinical utilization of melatonin.

Bubenik GA; Blask DE; Brown GM; Maestroni GJ; Pang SF; Reiter RJ; Viswanathan M; Zisapel N Department of Zoology, University of Guelph, Ont., Canada. gbubenik@uoguelph.ca

Biol Signals Recept (Switzerland) Jul-Aug 1998, 7 (4) p195-219

This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immuno-hematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress-induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilization of melatonin for treatment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled-release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin-deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light-dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive organs. In a clinical study, melatonin has been used successfully as an effective female contraceptive with little side effects. Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood-brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity and hyperbaric oxygen exposure. In the digestive tract, melatonin reduced the incidence and severity of gastric ulcers and prevented severe symptoms of colitis, such as mucosal lesions and diarrhea. (227 Refs.)

Beta-carotene enhances natural killer cell activity in athymic mice.

Carlos TF; Riondel J; Mathieu J; Guiraud P; Mestries JC; Favier A Groupe de Recherches et d'Etudes des Pathologies Oxydatives (GREPO), Faculte de Pharmacie, La Tronche, France.

In Vivo (Greece) Jan-Feb 1997, 11 (1) p87-91

To study the effects of beta-carotene on Natural Killer (NK) cells, we chose athymic mice whose spleens have a higher percentage of NK cells than conventional mice. Preliminary studies conducted with beta-carotene given intraperitoneally to athymic mice xenografted with a small-cell lung carcinoma resulted in a slight but significant antiproliferative effect (unpublished observations). We speculated that such an activity of beta-carotene was related to its immunostimulating properties. NK cell activity in ungrafted athymic mice as influenced by beta-carotene was studied. Mice received beta-carotene intraperitoneally. Splenic NK cells were labelled with monoclonal antibody and numeration was completed by measurement of their functional activity against YAC-1 malignant cells with a 51Cr release assay. In addition, splenic lymphocytes were evaluated for their reduced glutathione (GSH) content. There was a non-significant increase in the number of NK cells in the spleen, however their killing capacity was significantly (p < 0.01) enhanced after beta-carotene treatment. Also the GSH content of splenic lymphocytes was significantly higher in beta-carotene treated mice. Comparison of the average body weights of treated animals and of their respective controls showed that treatment had no adverse effects.

Partners in defense, vitamin E and vitamin C.

Chan AC. Department of Biochemistry, Faculty of Medicine, University of Ottawa, ON, Canada.

Can J Physiol Pharmacol. 1993 Sep;71(9):725-31.

In addition to the enzymic mechanism of free-radical removal, essential nutrients that can scavenge free radicals, such as vitamins E and C, constitute a strong line of defense in retarding free radical induced cellular damage. Distinct pathways for the repair of oxidized vitamin E in human cells have been recently identified. Within 0.5 min after the addition of arachidonic acid to a human platelet homogenate, over half of the platelet vitamin E and added arachidonate were metabolized by platelet cyclooxygenase and lipoxygenase pathways. After adding nordihydroguaiaretic acid, a lipoxygenase inhibitor and a strong reductant, over 60% of the oxidized vitamin E was regenerated. To test other physiological, water-soluble reductants that may help regenerate vitamin E, eicosatetraynoic acid, a lipoxygenase inhibitor that is not an antioxidant, was used. In this system, both ascorbate and glutathione provided significant vitamin E regeneration. Kinetic analysis and studies of vitamin E regeneration in a protein-denaturing system revealed that ascorbate regenerates vitamin E by a nonenzymic mechanism, whereas glutathione regenerates vitamin E enzymatically. These studies suggest that significant interaction occurs between water- and lipid-soluble molecules at the membrane-cytosol interface and that vitamin C may function in vivo to repair the membrane-bound oxidized vitamin E.

Nutrition and immune responses.

Chandra RK

Can J Physiol Pharmacol 1983 Mar;61(3):290-4

Clinical and epidemiologic data suggest a causal relationship between nutritional deficiency and infection. Among other factors, impaired immune responses secondary to malnutrition increase susceptibility to infectious illness. Protein-energy undernutrition and deficiencies of iron, zinc, pyridoxine, and other nutrients depress a variety of immunity functions. Cell-mediated immunity, complement system, microbicidal activity of phagocytes, secretory antibody response, and antibody affinity are often decreased. Recent studies have revealed many metabolic and hormone alterations as well as changes in the number and function of lymphocyte subpopulations. Obesity also is associated with impaired cellular immune functions. Dietary factors may play a critical role in host resistance to disease.

Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects.

Chandra RK Memorial University of Newfoundland.

Lancet 1992 Nov 7;340(8828):1124-7

Ageing is associated with impaired immune responses and increased infection-related morbidity. This study assessed the effect of physiological amounts of vitamins and trace elements on immunocompetence and occurrence of infection-related illness. 96 independently living, healthy elderly individuals were randomly assigned to receive nutrient supplementation or placebo. Nutrient status and immunological variables were assessed at baseline and at 12 months, and the frequency of illness due to infection was ascertained. Subjects in the supplement group had higher numbers of certain T-cell subsets and natural killer cells, enhanced proliferation response to mitogen, increased interleukin-2 production, and higher antibody response and natural killer cell activity. These subjects were less likely than those in the placebo group to have illness due to infections (mean [SD] 23 [5] vs 48 [7] days per year, p = 0.002). Supplementation with a modest physiological amount of micronutrients improves immunity and decreases the risk of infection in old age.

Nutrition and immunology: from the clinic to cellular biology and back again.

Chandra RK Department of Pediatrics and Medicine, Memorial University of Newfoundland, Canada. rchandra@morgan.ucs.mun.ca

Proc Nutr Soc 1999 Aug;58(3):681-3

Diet and immunity have been known to be linked to each other for centuries. In the last 30 years systematic studies have confirmed that nutrient deficiencies impair immune response and lead to frequent severe infections resulting in increased mortality, especially in children. Protein-energy malnutrition results in reduced number and functions of T-cells, phagocytic cells and secretory immunoglobulin A antibody response. In addition, levels of many complement components are reduced. Similar findings have been reported for moderate deficiencies of individual nutrients such as trace minerals and vitamins, particularly Zn, Fe, Se, vitamins A, B6, C and E. For example, Zn deficiency is associated with profound impairment of cell-mediated immunity such as lymphocyte stimulation response, decreased CD4+:CD8+ cells, and decreased chemotaxis of phagocytes. In addition, the level of thymulin, which is a Zn-dependent hormone, is markedly decreased. The use of nutrient supplements, singly or in combination, stimulates immune response and may result in fewer infections, particularly in the elderly, low-birth-weight infants and malnourished critically-ill patients in hospitals. The interactions between nutrition and the immune system are of clinical, practical and public health importance.

Numerical and functional deficiency of suppressor T cells precedes development of atopic eczema.

Chandra RK, Baker M

Lancet 1983 Dec 17;2(8364):1393-4

Immunoregulatory T cells were studied quantitatively and functionally at age 1-2 months in 30 symptom-free infants with family history of atopic disease and in 30 infants with no such history. The infants were followed up for 24-37 months (mean 28.2 months) to see whether clinical atopic disease was expressed. In infants in whom atopic eczema subsequently developed, numbers of T8-positive cells were reduced, the T4/T8 ratio was raised, and functional suppressor activity was lower than normal. These findings indicate that a defect of T-cell regulation precedes clinical atopic disease and is of primary pathogenetic importance.

Nutrition, immune response, and outcome.

Chandra S, Chandra RK

Prog Food Nutr Sci 1986;10(1-2):1-65

The immune system plays a key role in the body's ability to fight infection and reduce the risk of developing tumors, autoimmune and degenerative disease. Nutritional deficiencies and excesses influence various components of the immune system. Early studies investigating the association between nutrition and immunity focused on generalized protein-energy malnutrition, particularly in children in developing countries. The extent of immunological impairment depends not only on the severity of malnutrition but on the presence of infection and on the age of onset of nutritional deprivation, among other factors. In industrialized nations, immune function has been shown to be compromised in many malnourished hospitalized patients, small-for-gestational age infants, and the elderly. Obesity also may adversely influence immune function. Imbalances of single nutrients are relatively uncommon in humans, and investigations of protein and amino acids and specific vitamins, minerals, and trace elements generally are carried out in experimental animals. Deficiencies of protein and some amino acids, as well as vitamins A, E, B6 and folate, are associated with reduced immunocompetence. In contrast, excessive intake of fat, in particular polyunsaturated fatty acids (e.g. linoleic and arachidonic acids), iron, and vitamin E are immunosuppressive. Trace elements modulate immune responses through their critical role in enzyme activity. Both deficiency and excess of trace elements have been recognized. Although dietary requirements of most of these elements are met by a balanced diet, there are certain population groups and specific disease states which are likely to be associated with deficiency of one or more of these essential elements. The role of trace elements in maintenance of immune function and their causal role in secondary immunodeficiency is increasingly being recognized. There is growing research concerning the role of zinc, copper, selenium, and other elements in immunity and the mechanisms that underlie such roles. The problem of interaction of trace elements and immunity is a complex one because of the frequently associated other nutritional deficiencies, the presence of clinical or subclinical infections which in themselves have a significant effect on immunity, and finally the altered metabolism due to the underlying disease. There are many practical applications of our recently acquired knowledge regarding nutritional regulation of immunity.

Serum thymic factor activity in deficiencies of calories, zinc, vitamin A and pyridoxine.

Chandra RK, Heresi G, Au B

Clin Exp Immunol 1980 Nov;42(2):332-5

Cell-mediated immunity is invariably impaired in protein-energy malnutrition. The effect of selected nutrient deficiencies on serum thymic factor activity was assessed in deprived rats and pair-fed controls. Deficits of calories, zinc or pyridoxine resulted in significant lowering of serum thymic factor activity whereas vitamin A deficiency did not have any effect. It is suggested that variants nutrients modulate different steps of cell-mediated immunity and that reduced thymic hormone activity may be the underlying mechanism of impaired immunity in some but not all nutritional deficiencies.

Nutrition of the elderly.

Chandra RK, Imbach A, Moore C, Skelton D, Woolcott D Department of Medicine, Memorial University of Newfoundland, St. John's.

Can. Med. Assoc. J. (CMAJ) 1991 Dec 1; 145(11): 1475-87.

The progressively increasing number of elderly people in the Canadian population and the disproportionate expenditure on their health care has stimulated interest in prevention of common illnesses observed in this age group. It is now recognized that nutrition plays an important role in health status, and both undernutrition and overnutrition are associated with greater risk of morbidity and mortality. Nutritional problems in the elderly can be suspected if there are several high-risk factors present--for example, living alone, physical or mental disability, recent loss of spouse or friend, weight loss, use of multiple medications, poverty, and high consumption of alcohol. Physical examination, anthropometry, and measurements of serum albumin levels and hemoglobin and lymphocyte counts are simple but helpful tools in confirming the presence of nutritional disorders. The prevention and correction of nutritional problems is likely to prove beneficial in the management of common geriatric illnesses. In these efforts, it is desirable to have a team approach in which the physician, the dietitian and the nurse each have a defined interactive role. Home care support services are important adjuncts in continuing care. Nutrition should receive a greater emphasis in the training of physicians and other health professionals.

Zinc and immunity.

Chandra, R.K., McBean, L.D.

Nutrition 1994 Jan-Feb; 10(1): 7-80.

No abstract available.

Enhancing immunity by dietary consumption of a probiotic lactic acid bacterium (Bifidobacterium lactis HN019): optimization and definition of cellular immune responses.

Chiang BL, Sheih YH, Wang LH, Liao CK, Gill HS. College of Medicine, National Taiwan University, Taipei, Taiwan.

Eur J Clin Nutr 2000 Nov;54(11):849-55

OBJECTIVE: To define the cellular basis for immune enhancement by a probiotic lactic acid bacteria strain (Bifidobacterium lactis HN019); and to determine whether immune enhancement can be optimized by delivery in oligosaccharide-enriched low-fat milk. DESIGN: A double-blind, three-stage before-and-after intervention trial. SETTING: Taipei Medical College Hospital, Taipei, Taiwan. SUBJECTS: Fifty healthy Taiwanese citizens (age range 41-81; median 60) randomly allocated to two groups. INTERVENTIONS: In stage 1 (run-in control stage) all subjects consumed reconstituted low-fat milk (LFM) for 3 weeks; in stage 2 (probiotic intervention) subjects consumed B. lactis in LFM (group A) or B. lactis in lactose-hydrolysed LFM (group B) for 3 weeks; in stage 3 all subjects returned to non-supplemented LFM for a further 3 weeks (washout stage). The innate immune functions of two different leucocyte types (polymorphonuclear (PMN) cells and natural killer (NK) cells) were assessed at four time points via in vitro analyses on peripheral blood samples. RESULTS: While consumption of LFM alone had no significant effect on immune responses, stage 2 results indicated significantly enhanced PMN cell phagocytosis and NK cell tumour killing activity following consumption of milk containing B. lactis. These increases levelled off following cessation of B. lactis consumption, but remained above the pre-treatment values. Increases in PMN and NK cell activity were greatest among subjects who consumed B. lactis in lactose-hydrolysed LFM. CONCLUSIONS: Dietary consumption of the probiotic bacterium B. lactis HN019 enhanced immune function of two different types of leucocytes; the degree of enhancement was increased by consuming B. lactis in an oligosaccharide-rich substrate. SPONSORSHIP: Financial support was provided by the New Zealand Dairy Board.

Biological and health implications of toxic heavy metal and essential trace element interactions.

Chowdhury BA, Chandra RK.

Prog Food Nutr Sci. 1987;11(1):55-113.

Human civilization and a concomitant increase in industrial activity has gradually redistributed many toxic metals from the earth's crust to the environment and increased the possibility of human exposure. Among the various toxic elements, heavy metals cadmium, lead, and mercury are specially prevalent in nature due to their high industrial use. These metals serve no biological function and their presence in tissues reflects contact of the organism with its environment. They are cumulative poison, and are toxic even at low dose. Studies of metabolism and toxicity of these elements have revealed important interactions between them and some essential dietary elements like calcium, zinc, iron, selenium, copper, chromium, and manganese. In general, a deficiency of these essential elements increases toxicity of heavy metals, whereas an excess appears to be protective. While most of the observations are on laboratory animals, limited human data are in agreement with the results of animal experiments. These suggest that the dietary presence of the essential elements may contribute to the protection of man and animal from the effects of heavy metal exposure, while their deficiency may increase toxicity. Appropriate dietary manipulation thus may be valuable in the prevention and treatment of heavy metal toxicity.

Natural killer cells from aging mice treated with extracts from Echinacea purpurea are quantitatively and functionally rejuvenated.

Currier NL, Miller SC. Department of Anatomy and Cell Biology, McGill University, H3A 2B2, Montreal, Canada.

Exp Gerontol. 2000 Aug;35(5):627-39.

A growing body of anecdotal evidence in young and adult humans suggests that certain phytochemicals have the capacity to ameliorate tumors and reduce infections, especially those mediated by virus, in vivo. These indications prompted us, therefore, to investigate the potentially immuno-stimulating effect of one such phytocompound, Echinacea purpurea, on natural killer (NK) cells since these cells are active in spontaneous, non-specific immunity against neoplasms and virus-mediated infections. We elected to study aging mice, since, at this stage of life, like humans, the above-mentioned afflictions increase in frequency. We had previously found that neither the cytokine, interleukin-2, nor the pharmacological agent, indomethacin, both potent stimulators of NK cell numbers/function in younger adult mice, was effective in stimulating NK cells in elderly mice. The present study was designed to assess the numbers/production of NK cells in the spleen and bone marrow of aging, normal mice, after in vivo dietary administration of E. purpurea (14 days), or, after injection of thyroxin, a stimulant of NK cell function (10 days). Immunoperoxidase labeling techniques, coupled with hematologic tetrachrome staining were used to identify NK cells in both the spleen (primary site of NK cell function) and the bone marrow (site of NK cell generation). Double immunofluorscence staining, employing propidium iodide, was used to assess NK cell lytic function. Our results revealed that E. purpurea, but not thyroxin, had the capacity to increase NK cell numbers, in aging mice, reflecting increased new NK cell production in their bone marrow generation site, leading to an increase in the absolute numbers of NK cells in the spleen, their primary destiny. The E. purpurea-mediated increase in NK cell numbers was indeed paralleled by an increase in their anti-tumor, lytic functional capacity. Collectively, the data indicate that E. purpurea, at least, and possibly other plant compounds, appear to contain phytochemicals capable of stimulating de novo production of NK cells, as well as augmenting their cytolytic function, in animals of advanced age.

Dehydroepiandrosterone (DHEA) treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection.

Danenberg HD; Ben-Yehuda A; Zakay-Rones Z; Friedman G

Vaccine (England) 1995, 13 (15) p1445-8

Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity. Recently it was suggested that its age-associated decline is related with immunosenescence. To examine whether DHEA administration could effectively reverse the age-associated decline of immunity against influenza vaccine, aged mice were simultaneously vaccinated and treated with DHEA. Reversal of the age-associated decline and a significant constant increase of humoral response was observed in treated mice. Increased resistance to post-vaccination intranasal challenge with live influenza virus was observed in DHEA-treated aged mice. Thus, DHEA treatment overcame the age-related defect in the immunity of old mice against influenza.

Nutrients and immune responses.

Delafuente JC. Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville.

Rheum Dis Clin North Am 1991 May;17(2):203-12

A wide spectrum of nutritional deficiencies, ranging from trace elements to protein, can impair normal immunologic functions. Repletion of deficient nutrients generally will restore the immune response. Under some experimental conditions, single nutrient supplementation boosts immunity; however, some mega-dose therapies have been shown to suppress the immune response. Adequate nutrition is essential for maintaining the integrity of the immune system.

Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine.

De Simone C; Famularo G; Tzantzoglou S; Trinchieri V; Moretti S; Sorice F

AIDS (United States) May 1994, 8 (5) p655-60

OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4-N-trimethyl-am monio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine.

DESIGN: Immunopharmacologic study.

METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation.

RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels.

CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.

Vitamins and immunity: II. Influence of L-carnitine on the immune system.

De Simone C, Ferrari M, Lozzi A, Meli D, Ricca D, Sorice F.

Acta Vitaminol Enzymol. 1982;4(1-2):135-40.

Vitamin A affects the antibody responses and may affect phagocytic function and properdin levels. Pyridoxine deficiency impairs nucleic acid synthesis and depresses antibody formation, delayed hypersensitivity reactions and the ability of phagocytes to kill bacteria. Pantothenic acid deficiency impairs antibody formation. Vitamin C deficiency increases the incidence of infection, primary by a negative influence on reparative processes. Deficiencies of other vitamins either have not been sufficiently studied or have a variable effect. Moreover, even substances which for their biosynthesis require an adequate vitamin supplementation may exert immunomodulatory influences. With this respect the authors report their results on the influence of L-carnitine on the immune system. L-carnitine increases the proliferative responses of both murine and human lymphocyte following mitogenic stimulation and increase polymorphonuclear chemotaxis. Furthermore, L-carnitine, even at minimal concentrations, neutralizes the lipid induced immunosuppression.

High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients.

De Simone C, Tzantzoglou S, Famularo G, Moretti S, Paoletti F, Vullo V, Delia S. Universita di L'Aquila, Italy.

Immunopharmacol Immunotoxicol. 1993 Jan;15(1):1-12.

Several reports indicate that systemic carnitine deficiency could occur in acquired immunodeficiency disease syndrome (AIDS), and that primary and secondary carnitine deficiency leads to critical metabolic dysfunctions. L-carnitine supplementation to peripheral blood mononuclear cells (PBMCs) of AIDS patients resulted in significant enhancement of the phytohemagglutinin (PHA)-driven proliferative response. High dose L-carnitine administration (6 gr per day for two weeks) to AIDS patients treated with zidovudine also led to increased PBMCs proliferation and reduced blood levels of triglycerides. In addition, a reduction of beta 2-microglobulin serum levels as well as circulating tumor necrosis factor (TNF)-alpha, mostly in patients exhibiting highly elevated levels, were found at the end of the treatment period. Our data suggest that in vivo L-carnitine could prove useful in ameliorating both the immune response and lipid metabolism in patients with AIDS, irrespective of initial serum carnitines levels. The mechanism(s) accounting for the observed results are currently not clear. Further studies are needed to confirm the hypothesis that L-carnitine affects the expression of HIV-induced cytokine.

Vitamins and immunity: II. Influenceof L-carnitine on the immune system.

De Simone C; Ferrari M; Lozzi A; Meli D; Ricca D; Sorice F

Acta Vitaminol Enzymol (Italy) 1982, 4 (1-2)

Vitamin A affects the antibody responses and may affect phagocytic function and properdin levels. Pyridoxine deficiency impairs nucleic acid synthesis and depresses antibody formation, delayed hypersensitivity reactions and the ability of phagocytes to kill bacteria. Pantothenic acid deficiency impairs antibody formation. Vitamin-C deficiency increases the incidence of infection, primary by a negative influence on reparative processes. Deficiencies of other vitamins either have not been sufficiently studied or have a variable effect. Moreover, even substances which for their biosynthesis require an adequate vitamin supplementation may exert immunomodulatory influences. With this respect the authors report their results on the influence of L-carnitine on the immune system. L-carnitine increases the proliferative responses of both murine and human lymphocyte following mitogenic stimulation and increase polymorphonuclear chemotaxis. Furthermore, L-carnitine, even at minimal concentrations, neutralizes the lipid induced immunosuppression.

Serum IL-6 level and the development of disability in older persons.

Ferrucci L, Harris TB, Guralnik JM, Tracy RP, Corti MC, Cohen HJ, Penninx B, Pahor M, Wallace R, Havlik RJ. Geriatric Department, I Fraticini, National Research Institute (INRCA), Florence, Italy.

J Am Geriatr Soc 1999 Jun;47(6):639-46

BACKGROUND: The serum concentration of interleukin 6 (IL-6), a cytokine that plays a central role in inflammation, increases with age. Because inflammation is a component of many age-associated chronic diseases, which often cause disability, high circulating levels of IL-6 may contribute to functional decline in old age. We tested the hypothesis that high levels of IL-6 predict future disability in older persons who are not disabled. METHODS: Participants at the sixth annual follow-up of the Iowa site of the Established Populations for Epidemiologic studies of the Elderly aged 71 years or older were considered eligible for this study if they had no disability in regard to mobility or in selected activities of daily living (ADL), and they were re-interviewed 4 years later. Incident cases of mobility-disability and of ADL-disability were identified based on responses at the follow-up interview. Measures of IL-6 were obtained from specimens collected at baseline from the 283 participants who developed any disability and from 350 participants selected randomly (46.9%) from those who continued to be non-disabled. FINDINGS: Participants in the highest IL-6 tertile were 1.76 (95% CI, 1.17-2.64) times more likely to develop at least mobility-disability and 1.62 (95% CI, 1.02-2.60) times more likely to develop mobility plus ADL-disability compared with to the lowest IL-6 tertile. The strength of this association was almost unchanged after adjusting for multiple confounders. The increased risk of mobility-disability over the full spectrum of IL-6 concentration was nonlinear, with the risk rising rapidly beyond plasma levels of 2.5 pg/mL. INTERPRETATION: Higher circulating levels of IL-6 predict disability onset in older persons. This may be attributable to a direct effect of IL-6 on muscle atrophy and/or to the pathophysiologic role played by IL-6 in specific diseases.

Immunological and clinical effect of long-term oral treatment with RU 41740 in patients with chronic bronchitis: double-blind trial long-term versus standard dose regimen.

Fietta AM, Merlini C, Uccelli M, Gialdroni Grassi G, Grassi C. Chair of Chemotherapy, University of Pavia, IRCCS, Policlinico S. Matteo, Italy.

Respiration. 1992;59(5):253-8.

The immunological and clinical effects of two oral treatment schedules of RU 41740 (standard for 3 months vs. long-term for 6 months) were assessed in 40 patients with chronic bronchitis by a controlled, double-blind, randomized trial. Both treatments significantly improved phagocytosis index of both neutrophils and monocytes, and the phagocytosis frequency and the candidacidal activity of neutrophils, showing the maximum stimulation at the end of the third course of treatment. Both treatment schedules reduced the number and the duration of infectious exacerbations of chronic bronchitis with respect to those observed in the corresponding period of the previous year. However, no significant difference between standard and long-term treatment with RU 41740 was found with respect to the immunological and clinical effect and tolerability.

The activities of coenzyme Q10 and vitamin B6 for immune responses.

Folkers K, Morita M, McRee J Jr Institute for Biomedical Research, University of Texas, Austin 78712.

Biochem Biophys Res Commun 1993 May 28;193(1):88-92

Coenzyme Q10 (CoQ10) and vitamin B6 (pyridoxine) have been administered together and separately to three groups of human subjects. The blood levels of CoQ10 increased (p < 0.001) when CoQ10 and pyridoxine were administered together and when CoQ10 was given alone. The blood levels of IgG increased when CoQ10 and pyridoxine were administered together (p < 0.01) and when CoQ10 was administered alone (p < 0.05). The blood levels of T4-lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.01) and separately (p < 0.001). The ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.001) and separately (p < 0.05). These increases in IgG and T4-lymphocytes with CoQ10 and vitamin B6 are clinically important for trials on AIDS, other infectious diseases, and on cancer.

Increase in levels of IgG in serum of patients treated with coenzyme Q10.

Folkers, K., Shizukuishi, S., Takemura, K., Drzewoski, J., Richardson, P., Ellis, J., Kuzell, W.C.

Res. Commun. Chem. Pathol. Pharmacol. 1982 Nov; 38(2): 335-8.

No abstract available.

Research on coenzyme Q10 in clinical medicine and in immunomodulation.

Folkers K; Wolaniuk A

Drugs Exp Clin Res (Switzerland) 1985, 11 (8) p539-45

Coenzyme Q10 (CoQ10) is a redox component in the respiratory chain. CoQ10 is necessary for human life to exist; and a deficiency can be contributory to ill health and disease. A deficiency of CoQ10 in myocardial disease has been found and controlled therapeutic trials have established CoQ10 as a major advance in the therapy of resistant myocardial failure. The cardiotoxicity of adriamycin, used in treatment modalities of cancer, is significantly reduced by CoQ10, apparently because the side-effects of adriamycin include inhibition of mitochondrial CoQ10 enzymes. Models of the immune system including phagocytic rate, circulating antibody level, neoplasia, viral and parasitic infections were used to demonstrate that CoQ10 is an immunomodulating agent. It was concluded that CoQ10, at the mitochondrial level, is essential for the optimal function of the immune system.

Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances.

Franceschi C, Cossarizza A, Troiano L, Salati R, Monti D Institute of General Pathology, University of Modena, Italy.

Int J Clin Pharmacol Res 1990;10(1-2):53-7

Several immune parameters--particularly T-cell dependent immune responses--are altered in aged subjects. To test the hypothesis that they may be the consequence of more general age-related lymphocyte biochemical alterations, and particularly of the energy producing system, the effect of L-carnitine and acetyl-L-carnitine on cell proliferation was studied in peripheral blood lymphocytes from donors of different ages. The results showed that phytohaemagglutinin-induced peripheral blood lymphocyte proliferation was markedly increased in L-carnitine- or acetyl-L-carnitine-preloaded lymphocytes from young and especially from old subjects. Cells from aged subjects considerably improved their defective proliferative capability. Preliminary observations suggest that L-carnitine-preloading also protected peripheral blood lymphocytes from old donors when such cells were exposed to an oxidative stress.

Immunomodulatory and Anti-Cancer Properties of MGN-3, a Modified Xylose from Rice Bran, in 5 Patients with Breast Cancer (abstract).

Ghoneum, M.

Presented at the American Association for Cancer Research, Special Conference, Baltimore, MD, November 5-8, 1995.

Enhancement of human natural killer cell activity by modified arabinoxylane from rice bran (MGN-3)

Ghoneum M. M. Ghoneum, Drew University Medicine and Science, Department of Otolaryngology, 1621 East 120th Street, Los Angeles, CA 90059 United States International Journal of Immunotherapy ( Switzerland ) 1998 , 14/2 (89-99)

Arabinoxylane from rice bran (MGN-3) was examined for its augmentory effect on human NK (NK) cell activity in vivo and in vitro. Twenty-four individuals were given MGN-3 orally at three different concentrations: 15, 30 and 45 mg/kg/day for 2 months. Peripheral blood lymphocyte-NK cell activity was tested by sup 5sup 1Cr release assay against K562 and Raji tumor cells at 1 week, 1 month and 2 months posttreatment and results were compared with baseline NK activity. Treatment with MGN-3 enhanced NK activity against K562 tumor cells at all concentrations used. In a dose-dependent manner, MGN-3 at 15 mg/kg/day increased NK activity after 1 month posttreatment (twofold over control value), while significant induction of NK activity at 30 mg/kg/day was detected as early as 1 week posttreatment (three times control value). NK cell activity continued to increase with continuation of treatment and peaked (fivefold) at 2 months (end of treatment period). Increasing the concentration to 45 mg/kg/day showed similar trends in NK activity, however the magnitude in values was higher than for 30 mg/kg/day. After discontinuation of treatment, NK activity declined and returned to baseline value (14 lytic units) at 1 month. Enhanced NK activity was associated with an increase in the cytotoxic reactivity against the resistant Raji cell line. MGN-3 at 45 mg/kg/day showed a significant increase in NK activity after 1 week (eightfold) and peaked at 2 months posttreatment (27 times that of baseline). Culture of peripheral blood lymphocytes (PBL) with MGN-3 for 16 h demonstrated a 1.3 to 1.5 times increase in NK activity over control value. The mechanism by which MGN-3 increases NK activity was examined and showed no change in cluster of differentiation (CD) 16sup + and CD56sup + CD3sup - of MGN-3-activated NK cells as compared with baseline value; a fourfold increase in the binding capacity of NK to tumor cell targets as compared with baseline value; and a significant increase in the production of interferon-gamma (340-580 pg/ml) postculture of PBL with MGN-3 at concentrations of 25-100 mug/ml. Thus, MGN-3 seems to act as a potent immunomodulator causing augmentation of NK cell activity, and with the absence of notable side-effects, MGN-3 could be used as a new biological response modifier (BRM) having possible therapeutic effects against cancer.

NK Immunomodulatory Function in 27 Cancer Patients by MGN-3, a Modified Arabinoxylane from Rice Bran (abstract).

Ghoneum, M., Namatalla, G.

Presented at the 87th Annual Meeting of the American Association for Cancer Research, Washington, D.C., April 20-24, 1996.

Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes.

Gill HS, Rutherfurd KJ, Cross ML. Milk & Health Research Centre, Institute of Food, Nutrition and Human Health, Massey University, Palmerston North, New Zealand. H.S.Gill@massey.ac.nz

J Clin Immunol 2001 Jul;21(4):264-71

Many elderly subjects are at increased risk of infectious and noninfectious diseases due to an age-related decline in lymphoid cell activity (immunosenescence). Noninvasive means of enhancing cellular immunity are therefore desirable in the elderly. Previous reports have suggested that dietary supplementation could represent an effective means of enhancing the activity of circulating natural killer (NK) cells in the elderly. In the present study, we have conducted a pre-post intervention trial to determine the impact of dietary supplementation with probiotic lactic acid bacteria (LAB) on peripheral blood NK cell activity in healthy elderly subjects. Twenty-seven volunteers consumed low-fat/low-lactose milk supplemented with known immunostimulatory LAB strains (Lactobacillus rhamnosus HN001 or Bifidobacterium lactis HN019) for a period of 3 weeks. A dietary run-in of milk alone was shown to have no significant effect on NK cells. In contrast, the proportion of CD56-positive lymphocytes in peripheral circulation was higher following consumption of either LAB strain, and ex vivo PBMC tumoricidal activity against K562 cells was also increased. Supplementation with HN001 or HN019 increased tumoricidal activity by an average of 101 and 62%, respectively; these increases were significantly correlated with age, with subjects older than 70 years experiencing significantly greater improvements than those under 70 years. These results demonstrate that dietary consumption of probiotic LAB in a milk-based diet may offer benefit to elderly consumers to combat some of the deleterious effects of immunosenescence on cellular immunity.

Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019.

Gill HS, Rutherfurd KJ, Cross ML, Gopal PK. Milk & Health Research Centre, Massey University, New Zealand, and the New Zealand Dairy Research Institute, Palmerston North, New Zealand.

Am J Clin Nutr 2001 Dec;74(6):833-9

BACKGROUND: The aging process can lead to a decline in cellular immunity. Therefore, the elderly could benefit from safe and effective interventions that restore cellular immune functions. OBJECTIVE: We determined whether dietary supplementation with the known immunostimulating probiotic Bifidobacterium lactis HN019 could enhance aspects of cellular immunity in elderly subjects. DESIGN: Thirty healthy elderly volunteers (age range: 63-84 y; median: 69 y) participated in a 3-stage dietary supplementation trial lasting 9 wk. During stage 1 (run-in), subjects consumed low-fat milk (200 mL twice daily for 3 wk) as a base-diet control. During stage 2 (intervention), they consumed milk supplemented with B. lactis HN019 in a typical dose (5 x 10(10) organisms/d) or a low dose (5 x 10(9) organisms/d) for 3 wk. During stage 3 (washout), they consumed low-fat milk for 3 wk. Changes in the relative proportions of leukocyte subsets and ex vivo leukocyte phagocytic and tumor-cell-killing activity were determined longitudinally by assaying peripheral blood samples. RESULTS: Increases in the proportions of total, helper (CD4(+)), and activated (CD25(+)) T lymphocytes and natural killer cells were measured in the subjects' blood after consumption of B. lactis HN019. The ex vivo phagocytic capacity of mononuclear and polymorphonuclear phagocytes and the tumoricidal activity of natural killer cells were also elevated after B. lactis HN019 consumption. The greatest changes in immunity were found in subjects who had poor pretreatment immune responses. In general, the 2 doses of B. lactis HN019 had similar effectiveness. CONCLUSION:B. lactis HN019 could be an effective probiotic dietary supplement for enhancing some aspects of cellular immunity in the elderly.

Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network.

Girodon F, Galan P, Monget AL, Boutron-Ruault MC, Brunet-Lecomte P, Preziosi P, Arnaud J, Manuguerra JC, Herchberg S. Scientific and Technical Institute for Foods and Nutrition, Conservatiore National des Arts et Mettiers, Paris, France.

Arch Intern Med. 1999 Apr 12;159(7):748-54.

BACKGROUND: Antioxidant supplementation is thought to improve immunity and thereby reduce infectious morbidity. However, few large trials in elderly people have been conducted that include end points for clinical variables. OBJECTIVE: To determine the effects of long-term daily supplementation with trace elements (zinc sulfate and selenium sulfide) or vitamins (beta carotene, ascorbic acid, and vitamin E) on immunity and the incidence of infections in institutionalized elderly people. METHODS: This randomized, double-blind, placebo-controlled intervention study included 725 institutionalized elderly patients (>65 years) from 25 geriatric centers in France. Patients received an oral daily supplement of nutritional doses of trace elements (zinc and selenium sulfide) or vitamins (beta carotene, ascorbic acid, and vitamin E) or a placebo within a 2 x 2 factorial design for 2 years. MAIN OUTCOME MEASURES: Delayed-type hypersensitivity skin response, humoral response to influenza vaccine, and infectious morbidity and mortality. RESULTS: Correction of specific nutrient deficiencies was observed after 6 months of supplementation and was maintained for the first year, during which there was no effect of any treatment on delayed-type hypersensitivity skin response. Antibody titers after influenza vaccine were higher in groups that received trace elements alone or associated with vitamins, whereas the vitamin group had significantly lower antibody titers (P<.05). The number of patients without respiratory tract infections during the study was higher in groups that received trace elements (P = .06). Supplementation with neither trace elements nor vitamins significantly reduced the incidence of urogenital infections. Survival analysis for the 2 years did not show any differences between the 4 groups. CONCLUSIONS: Low-dose supplementation of zinc and selenium provides significant improvement in elderly patients by increasing the humoral response after vaccination and could have considerable public health importance by reducing morbidity from respiratory tract infections.

Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial.

Girodon F, Lombard M, Galan P, Brunet-Lecomte P, Monget AL, Arnaud J, Preziosi P, Hercberg S. Institut Scientifique et Technique de la Nutrition et de l'Alimentation, Paris, France.

Ann Nutr Metab. 1997;41(2):98-107.

To determine the impact of a trace element and vitamin supplementation on infectious morbidity, a double-blind controlled trial was performed on 81 elderly subjects in a geriatric center during a 2-year period. Subjects were randomly assigned to one of four treatment groups, and received daily: placebo; trace elements/zinc 20 mg; selenium 100 micrograms); vitamins (vitamin C 120 mg; beta-carotene 6 mg; alpha-tocopherol 15 mg); or a combination of trace elements and vitamins at equal doses. (1) Before supplementation, low serum values in vitamin C, folate, zinc and selenium were observed in more than two thirds of the patients. (2) After 6 months of supplementation, a significant increase in vitamin and trace element serum levels was obtained in the corresponding treatment groups: a plateau was then observed for the whole study. (3) Subjects who received trace elements (zinc and selenium) alone or associated with vitamins had significantly less infectious events during the 2 years of supplementation. These results indicate that supplementation with low doses of vitamins and trace elements is able to rapidly correct corresponding deficiencies in the institutionalized elderly. Moreover, zinc and selenium reduced infectious events.

Kuby Immunology, Fourth Edition 2000.

Goldsby, R.A., Kindt, T.J., Osborne, B.A.

New York: W.H. Freeman.

Effect of antioxidative vitamins on immune function with clinical applications.

Grimble RF Institute of Human Nutrition, University of Southampton, U.K.

Int J Vitam Nutr Res (Switzerland) 1997, 67 (5) p312-20

Infection and trauma cause inflammatory stress in patients. Tissue damage, enhanced inflammatory mediator production and suppressed lymphocyte function may occur as a consequence. The antioxidative vitamins, ascorbic acid and the tocopherols, are important not only for limiting tissue damage but also in preventing increased cytokine production which is a consequence of excessive activation of NF kappa B. Glutathione is a major endogenous antioxidant and is important for lymphocyte replication. Two vitamins, vitamin B6 and riboflavin participate in the maintainance of glutathione status. The former vitamin acts as a cofactor in the synthesis of cysteine (the rate limiting precursor for glutathione biosynthesis) and the latter vitamin is a cofactor for glutathione reductase. Deficiencies in tocopherol, vitamin B6 and riboflavin reduce cell numbers in lymphoid tissues of experimental animals and produce functional abnormalities in the cell mediated immune response. Ascorbic acid and tocopherols exert anti-inflammatory effects in studies in man and animals. In humans, dietary supplementation with ascorbic acid, tocopherols and vitamin B6 enhances a number of aspects of lymphocyte function. The effect is most apparent in the elderly. (69 Refs.)

Micronutrient supplementation and immune function in the elderly

High K.P. Dr. K.P. High, Dept. of Int. Med./Infectious Dis., Wake Forest Univ. School of Medicine, 100 Medical Center Boulevard, Winston-Salem, NC 27157-1042 United States khigh@wfubmc.edu

Clinical Infectious Diseases 1999, 28/4 (717-722)

Immunologic function, particularly cell-mediated immunity, declines with age, contributing to the increased incidence of infectious diseases in the elderly. Nutrition may play a pivotal role in maintaining immune competence in older adults. Most studies to date have focused on micronutrient deficiencies and supplementation, sometimes using 'mega-dose' formulations. Multivitamin/mineral supplements or specific micronutrients such as zinc and vitamin E may be of value; however, data suggest there is likely a therapeutic range for many micronutrients, and oversupplementation may be harmful. Specific alterations of dietary lipids may also be useful for modulating immune responses in the elderly. This review summarizes the prevalence of vitamin and mineral deficiencies in older adults and highlights the outcomes of trials of micronutrient supplementation to augment immune function in the elderly.

Modulation of secretory immunoglobulin A in saliva; response to manipulation of mood.

Hucklebridge F, Lambert S, Clow A, Warburton DM, Evans PD, Sherwood N. Psychophysiology and Stress Research Group, Department of Biomedical Sciences, University of Westminster, London, UK. hucklef@wmin.ac.uk

Biol Psychol. 2000 May;53(1):25-35.

Secretory immunoglobulin A (sIgA) measured in saliva, an index of mucosal immunity, has repeatedly been shown to be sensitive to psychological variables. Chronic stress is downregulatory whereas an acute psychological challenge induces mobilisation. We examined whether an acute manipulation of mood to induce negative hedonic tone would be downregulatory, as in the chronic stress paradigm and further, whether induction of positive mood might have opposite effects. Two separate experiments were conducted. In the first, mood manipulation was by mental recall and in the second by music. For both sIgA concentration and sIgA secretion rate there was a significant elevation in response to the mood manipulation by recall regardless of hedonic tone. There was some evidence that for sIgA secretion rate the response was more pronounced for positive mood. Mood induction by music also resulted in significant elevations in sIgA concentration and secretion rate and responses were not distinguished by mood valence. None of the mood induction procedures was associated with changes in free cortisol. In these studies, we found no evidence that transient lowering of mood was downregulatory for salivary sIgA. The predominant finding was of sIgA mobilisation. [Preventive action of an immunomodulator on respiratory infections in elderly subjects] [Article in French]

Hugonot R, Gutierrez LM, Hugonot L. Hopital Necker-Enfants malades, Paris.

Presse Med. 1988 Jul 27;17(28):1445-9.

Three hundred and fourteen elderly subjects admitted to chronic medical centers were given either RU 41740 (n = 155) or a placebo (n = 159) at the rate of one course per month during three months. RU 41740 was administered in doses of 2 mg per day during 8 days in the first course and 1 mg per day during 8 days in the second and third courses. The subjects were followed up and regularly examined every three months for one year. The incidence of acute infectious episodes was evaluated in both groups. Compared to those patients who received the placebo, the number of subjects without infection was significantly higher in the treated group during the 0-6 months and the 0-9 months periods and during the 12 months of observation. The number of infectious episodes was reduced during the 0-3 months and 0-9 months periods and throughout the 12 months of the trial. The mean duration of pulmonary infections that occurred during the 0-6 and 0-9 months periods was reduced. Finally, there was a significant decrease in the duration of antibiotic therapy during the 0-3, 0-6, 0-9 months periods and during the 12 months of observation. The drug was well tolerated. This study showed that RU 41740 is effective in protecting elderly and therefore fragile subjects against respiratory infections.

Food allergy-or enterometabolic disorder?

Hunter, J.O.

Lancet 1991 Aug 24; 338(8765): 495-6.

No abstract available.

Nutritional factors in inflammatory bowel disease.

Hunter JO. Addenbrooke's Hospital, Gastroenterology Research Unit, Cambridge, UK.

Eur J Gastroenterol Hepatol. 1998 Mar;10(3):235-7.

During the past 20 years there has been growing interest in the importance of nutritional factors in the pathogenesis of inflammatory bowel disease. There are so far no definite links between ulcerative colitis and diet, but links with Crohn's disease have been studied by both epidemiologists and clinicians. Epidemiological studies, although retrospective, have suggested that patients with Crohn's disease eat more sugar and sweets that control individuals; however, when dietary sugar is restricted, there is little clinical benefit. The clinical approach to nutrition in Crohn's disease has been by the use of elemental diets, which will produce symptomatic and objective remission in up to 90% of compliant patients. Those who return to normal eating soon relapse but, in some studies, have enjoyed prolonged remission on exclusion diets. The foods excluded have been not sugar, but predominantly cereals, dairy products and yeast. Attention has now switched to the possible harmful role of fat in Crohn's disease. The efficacy of elemental feeds appears to depend not on the presentation of nitrogen but on the amount of long chain triglyceride present. Increases in recent years in the frequency of Crohn's disease in Japan have been correlated with increased dietary fat intake, and a recent study suggested that W-3 fatty acids, which are metabolized by immunomodulatory leukotrienes and prostaglandins, may have a beneficial role to play. The links between nutrition and Crohn's disease have now become strong and the role of fat may be the most exciting of all.

Modulation of cytokine production by dehydroepiandrosterone (DHEA) plus melatonin (MLT) supplementation of old mice.

Inserra P, Zhang Z, Ardestani SK, Araghi-Niknam M, Liang B, Jiang S, Shaw D, Molitor M, Elliott K, Watson RR. Arizona Prevention Center, University of Arizona, Tucson 87524, USA.

Proc Soc Exp Biol Med 1998 May;218(1):76-82

Tissue levels of the antioxidants melatonin (MLT) and dehydroepiandrosterone (DHEA) decline with age, and this decline is correlated with immune dysfunction. The aim of the current study is to determine whether hormone supplementation with MLT and DHEA together would synergize to reverse immune senescence. Old (16.5 months) female C57BL/6 mice were treated with DHEA, MLT, or DHEA + MLT. As expected, splenocytes were significantly (P < 0.05) higher in old mice as compared to young mice. DHEA, MLT, and DHEA + MLT significantly (P < 0.005) increased B cell proliferation in young mice. However, only MLT and DHEA + MLT significantly (P < 0.05) increased B cell proliferation in old mice. DHEA, MLT, and DHEA + MLT help to regulate immune function in aged female C57BL/6 mice by significantly (P < 0.05) increasing Th1 cytokines, IL-2, and IFN-gamma or significantly (P < 0.05) decreasing Th2 cytokines, IL-6, and IL-10, thus regulating cytokine production. DHEA and MLT effectively modulate suppressed Th1 cytokine and elevated Th2 cytokine production; however, their combined use produced only a limited additive effect.

Preventive nutrition: disease-specific dietary interventions for older adults.

Johnson K; Kligman EW Dept. of Family and Community Medicine, University of Arizona College of Medicine, Tucson.

Geriatrics Nov 1992, 47 (11) p39-40, 45-9

Disease prevention through dietary management is a cost-effective approach to promoting healthy aging. Fats, cholesterol, soluble fiber, and the trace elements copper and chromium affect the morbidity and mortality of CHD. Decreasing sodium and increasing potassium intake improves control of hypertension. Calcium and magnesium may also have a role in controlling hypertension. The antioxidant vitamins A and beta-carotene, vitamin C, vitamin E, and the trace mineral selenium may protect against types of cancer. A decrease in simple carbohydrates and an increase in soluble dietary fiber may normalize moderately elevated blood glucose levels. Deficiencies of zinc or iron diminish immune function . Adequate levels of calcium and vitamin D can help prevent senile osteoporosis in both older men and women. (27 Refs.)

Inhibition of intracellular cathepsin activities and suppression of immune responses mediated by helper T lymphocyte type-2 by peroral or intraperitoneal administration of vitamin B6.

Katunuma N, Matsui A, Endo K, Hanba J, Sato A, Nakano M, Yuto Y, Tada Y, Asao T, Himeno K, Maekawa Y, Inubushi T. Tokushima Bunri University, Institute for Health Sciences, Japan.

Biochem Biophys Res Commun 2000 May 27;272(1):151-5

We reported that pyridoxal phosphate (PAP), a coenzyme form of vitamin B6, strongly inhibits activities of cathepsin B and weakly inhibits those of cathepsins S, K, and C in vitro. Either intraperitoneal injection or peroral administration of medication doses of vitamin B6 in the diet caused dose-dependent inhibition of hepatic cathepsins B, L, S, and C, and the inhibition was exhibited much more significantly in the case of a high protein diet than in a low protein diet. Administration of vitamin B6 induced the suppression of immune responses against ovalbumin (OVA) mediated by helper T lymphocyte type-2, based on the suppression of antigen processing by cathepsin B inhibition, as in the case of CA-074 administration, a cathepsin B specific inhibitor. Ovalbumin-dependent production of immunoglobulins IgE, IgG1 and interleukin IL-4 was suppressed by administration of medication doses of pyridoxal (PA) or pyridoxine (PI), while the production of IgG2alpha and interferon (INF)-gamma mediated by helper T lymphocyte type 1 was not changed. Administration of medication doses of vitamin B6 caused the inhibition of intracellular cathepsin B activity due to suppression of the functions of helper T lymphocyte type-2.

Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men.

Khorram O, Vu L, Yen SS. Department of Reproductive Medicine, University of California, San Diego School of Medicine, USA.

J Gerontol A Biol Sci Med Sci 1997 Jan;52(1):M1-7

BACKGROUND: Substantial data from animal studies have demonstrated a stimulatory effect of dehydroepiandrosterone (DHEA) on immune function. However, little is known about the effects of DHEA on the human immune system. Since aging is associated with a decline in immune function and in DHEA production, we proposed that oral administration of DHEA to elderly men would result in activation of their immune system.

METHODS: Nine healthy age-advanced men (mean age of 63 years) with low DHEA-sulfate levels participated in this study. They were treated nightly with an oral placebo for 2 weeks followed by DHEA (50 mg) for 20 weeks. Fasting (0800h-0900h) blood samples were obtained at 4- to 8-week intervals for immune function studies and hormone determinations. Freshly isolated peripheral lymphocytes were used for flow cytometric identification of lymphocyte subsets, cells expressing the IL-2 receptor (IL-2R), mitogen stimulation studies, and for determining natural killer (NK) cell number and cytotoxicity. Levels of interleukin-2 (IL-2) and IL-6 secreted from cultured lymphocytes were determined under basal and mitogen stimulated conditions. Sera were analyzed for soluble IL-2 Receptor (sIL-2R) levels, insulin-like growth factor-I (IGF-I) and IGF binding protein-I (IGFBP-I) concentrations.

RESULTS: Baseline levels of serum DHEA sulfate (DHEAS), a stable marker of circulating DHEA levels, were 2 standard deviations below young adult values and increased 3-4 fold within 2 weeks. These levels were sustained throughout the duration of DHEA administration. When compared with placebo, DHEA administration resulted in a 20% increase (p < .01) in serum IGF-I, a decreasing trend in IGFBP-I, and a 32% increase in the ratio of IGF-I/IGFBP-I (p < .01). Activation of immune function occurred within 2-20 weeks of DHEA treatment. The number of monocytes increased significantly (p < .01) after 2 (45%) and 20 (35%) weeks of treatment. The population of B cells fluctuated with increases (p < .05) at 2 (35%) and 10 (29%) weeks of treatment. B cell mitogenic response increased 62% (p < .05) by 12 weeks unaccompanied by changes in serum IgG, IgA, and IgM levels. Total T cells and T cell subsets were unaltered. However, a 40% increase (p < .05) in T cell mitogenic response, 39% increase in cells expressing the IL-2R (CD25+) (p < .05), and 20% increase in serum sIL-2R levels (p < .01) were found at 12-20 weeks of DHEA treatment, suggesting a functional activation of T lymphocytes occurred. In vitro mitogen stimulated release of IL-2 and IL-6 was enhanced 50% (p < .05) and 30% (p < .01) respectively by 20 weeks of treatment without basal secretion being affected. NK cell number showed a 22-37% increase (p < .01) by 18-20 weeks of treatment with a concomitant 45% increase (p < .01) in cytotoxicity. There were no adverse effects noted with DHEA administration.

CONCLUSION: Administration of oral DHEA at a daily dose of 50 mg to age-advanced men with low serum DHEAS levels significantly activated immune function. The mechanism(s) to account for the immunoenhancing properties of DHEA are unclear. Consideration is given to the potential role of an increase in bioavailable IGF-I, which by virtue of its mitogenic effects on immune cell function, may mediate the DHEA effects. While extended studies are required, our findings suggest potential therapeutic benefits of DHEA in immunodeficient states.

Essential fatty acids, immune function, and exercise.

Konig D; Berg A; Weinstock C; Keul J; Northoff H Department of Rehabilitation, Prevention and Sports Medicine, Freiburg University Hospital, Germany.

Exerc Immunol Rev 1997, 3 p1-31

The immunologic response to exercise comprises numerous alterations within the immune system, but how these processes are regulated is still largely unknown. Exercise-related immunological changes include signs of inflammation, such as release of inflammatory mediators, activation of various white blood cell lines and complement, and induction of acute phase proteins. Nevertheless, signs of immunosuppression, such as decreased T and B cell function or impaired cytotoxic or phagocytic activity, can also be observed. Some data suggest that essential fatty acids help regulate inflammatory processes, modulating both cytokine release and the acute phase response. Positive effects of changing dietary essential fatty acids have been demonstrated in chronic inflammatory diseases. In contrast, little is known about the contribution of fatty acids to the exercise-induced immunologic reaction. Essential fatty acids may determine alterations within the immune system following exercise. Therefore, future studies are necessary to evaluate the influence of the fatty acid composition on the inflammatory or immunosuppressive component following heavy exertion. (236 Refs.)

Melatonin.

Kostogloy-Athanassiou, I.

Arch. Hellenic Med. 1998; 15(3): 281-306.

No abstract available.

[Administration of RU 41740, a preventive anti-infective immunomodulator in an acute respiratory episode. Synthesis of 3 clinical trials] [Article in French]

Lacaille F. Hopital Necker-Enfants malades, Paris.

Presse Med. 1988 Jul 27;17(28):1453-7.

In both adults and children RU 41740 exerts an immunomodulating effect and prevents recurrent respiratory infections. Patients with such infections frequently consult for acute episodes, and it was deemed necessary to evaluate the safety of the drug given concomitantly with antibiotic in acute infections. Three double-blind, drug versus placebo studies were conducted in fragile institutionalized or hospitalized patients. Antibiotics were administered simultaneously with RU 41740 in one group and with a placebo in another group. The studies performed by Albarede and Ollivier showed that in acute respiratory infections RU 41740 was well tolerated and resulted in a more rapid improvement of severity score. Grassi and al. studied chronic bronchitis patients admitted for acute on chronic episode. RU 41740 produced a more rapid improvement in the most severely ill patients, and it was well tolerated. It is concluded that RU 41740 can be initiated safely in acute episodes occurring in subjects with recurrent respiratory infections, and that it results in a faster improvement of clinical symptoms.

Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments.

Lesourd BM. Laboratoire d'Immunologie du vieillissement, Faculte de Medecine Pitie-Salpetriere, Paris, France.

Am J Clin Nutr 1997 Aug;66(2):478S-484S

Nutrition has a strong influence on the immune system of the elderly. Aging induces dysregulation of the immune system, mainly as a result of changes in cell-mediated immunity. Aging is associated with changes to the equilibrium of peripheral T and B lymphocyte subsets, such as decreases in the ratios of mature to immature, naive to memory, T helper 1 subset (TH1) to TH2, and CD5- to CD5+ cells. As a consequence, cell-mediated immune responses are weaker and neither cell-mediated nor humoral responses are as well adapted to the antigen stimulus. Undernutrition, common in aged populations, also induces lower immune responses, particularly in cell-mediated immunity. Protein-energy malnutrition is associated with decreased lymphocyte proliferation, reduced cytokine release, and lower antibody response to vaccines. Micronutrient deficits, namely of zinc, selenium, and vitamin B-6, all of which are prevalent in aged populations, have the same influence on immune responses. Because aging and malnutrition exert cumulative influences on immune responses, many elderly people have poor cell-mediated immune responses and are therefore at a high risk of infection. Nutritional therapy may improve immune responses of elderly patients with protein-energy malnutrition. Supplementation with high pharmacologic doses of a single nutrient (zinc or vitamin E) may be useful for improving immune responses of self-sufficient elderly people living at home. Therefore, nutritional deficiency must be treated in the elderly to reduce infectious risk and possibly slow the aging process.

Trace elements that act as antioxidants in parenteral micronutrition

Leung F.Y. Dr. F.Y. Leung, University Campus, London Health Sciences Centre, Department of Clinical Biochemistry, 339 Windermere Road, London, Ont. N6A 5A5

Canada Journal of Nutritional Biochemistry, 1998, 9/6 (304-307)

The trace elements - copper, manganese, selenium, and zinc - act as cofactors of antioxidant enzymes to protect the body from oxygen free radicals (OFR) that are produced during oxidative stress. It is necessary to maintain a balance between the harmful pro-oxidant components produced and the antioxidant compounds that counter these effects. A delicate balance also exists for the redox trace elements such as copper, which can initiate free radical reactions but is also a cofactor of Cu/Zn-superoxide dismutase, a free radical scavenging enzyme. Metal chelators such as ceruloplasmin play an important function to contain the reactive Cu ion. Similarly, transferrin and transferrin receptor maintain homeostatic control of iron, allowing little or no free iron to participate in formation of the reactive hydroxyl radical. Selenium is found to be most severely deficient in traumatized patients who need adequate supplementation during parenteral micronutrition to assist the free radical scavenging activity of glutathione peroxidase and the immune system .

The efficacy of echinacea compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: a randomized, double-blind placebo-controlled study.

Lindenmuth GF, Lindenmuth EB. Rest Haven-York, York College of Pennsylvania, USA.

J Altern Complement Med. 2000 Aug;6(4):327-34.

OBJECTIVES: The aim of this study was to determine the efficacy of an Echinacea compound herbal tea preparation (Echinacea Plus) given at early onset of cold or flu symptoms in a random assignment double-blind placebo-controlled study. DESIGN AND SUBJECTS: A total of 95 subjects with early symptoms of cold or flu (runny nose, scratchy throat, fever) were randomly assigned to receive Echinacea Plus tea five to six cups per day titrating to 1 over 5 days or placebo in a double-blind situation. Each participant completed a questionnaire 14 days after beginning the program. The efficacy, number of days the symptoms lasted, and number of days for change were measured with a self scoring questionnaire. RESULTS: The study period was 90 days (January 1, 1999 to March 30, 1999). There was a significant difference between the experimental group (Echinacea Plus) and control group (placebo) for all 3 questions measured: p < 0.001. There were no negative effects reported by any of the subjects in either group. CONCLUSIONS: Treatment with Echinacea Plus tea at early onset of cold or flu symptoms was effective for relieving these symptoms in a shorter period of time than a placebo.

Endocrine and immune effects of melatonin therapy in metastatic cancer patients.

Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F Divisione di Radioterapia Oncologica, Ospedale San Gerardo, Milano, Italy.

Eur J Cancer Clin Oncol 1989 May;25(5):789-95

Melatonin, the most important indole hormone produced by the pineal gland, appears to inhibit tumor growth; moreover, altered melatonin secretion has been reported in cancer patients. Despite these data, the possible use of melatonin in human neoplasms remains to be established. The aim of this clinical trial was to evaluate the therapeutic, immunological and endocrine effects of melatonin in patients with metastatic solid tumor, who did not respond to standard therapies. The study was carried out on 14 cancer patients (colon, six; lung, three; pancreas, two; liver, two; stomach, one). Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period in an oral dose of 10 mg daily in patients who had a remission, stable disease or an improvement in PS. Before and after the first 2 months of therapy, GH, somatomedin-C, beta-endorphin, melatonin blood levels and lymphocyte subpopulations were evaluated. A partial response was achieved in one case with cancer of the pancreas, with a duration of 18+ months; moreover, six patients had stable disease, while the other eight progressed. An evident improvement in PS was obtained in 8/14 patients. In patients who did not progress, T4/T8 mean ratio was significantly higher after than before melatonin therapy, while it decreased in patients who progressed. On the contrary, hormonal levels were not affected by melatonin administration. This study would suggest that melatonin may be of value in untreatable metastatic cancer patients, particularly in improving their PS and quality of life; moreover, based on its effects on the immune system, melatonin could be tested in association with other antitumor treatments.

Pineal-opioid system interactions in the control of immunoinflammatory responses.

Lissoni P, Barni S, Tancini G, Fossati V, Frigerio F Division of Radiation Oncology, San Gerardo Hospital, Monza, Milan,Italy.

Ann N Y Acad Sci 1994 Nov 25;741:191-6

Several studies have demonstrated involvement of the pineal gland in the regulation of neuropeptide secretion and activity. In particular, the existence of links between the pineal gland and the brain opioid system has been documented. Both opioid peptides and melatonin (MLT), the most investigated pineal hormone, play an important role in neuromodulation of the immunity. Moreover, the immune effects of MLT are mediated by endogenous opioid peptides, which may be produced by both the endocrine system and the immune cells. In addition, the immune dysfunctions that characterize some human diseases, such as cancer, depend not only on the immune system per se, but also at least in part, on altered secretion of immunomodulating neurohormones, including MLT and opioid peptides. Therefore, the exogenous administration of neurohormones could potentially improve the immune status in humans. The present study evaluates the effects of MLT on changes in the number of T lymphocytes, natural killer cells, and eosinophils induced by exogenous administration of interleukin-2 (IL-2). Macrophage activity was also evaluated by determining serum levels of its specific marker, neopterin. The study was performed in 90 patients with advanced solid neoplasms, who received IL-2 at a dose of 3 million IU/day subcutaneously for 6 days a week for 4 weeks plus MLT at a daily dose of 40 mg. Both drugs were given in the evening. The results were compared to those in 40 cancer patients treated with IL-2 alone. The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those who received IL-2 alone.

Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients.

Lissoni P; Brivio F; Brivio O; Fumagalli L; Gramazio F; Rossi M

J Biol Regul Homeost Agents (Italy) Jan-Mar 1995, 9 (1) p31-3

Surgery-induced immunosuppression could influence tumor/host interactions in surgically treated cancer patients. Previous studies have shown that high-dose IL-2 preoperative therapy may neutralize surgery-induced lymphocytopenia. Moreover, experimental studies have demonstrated that the immunomodulating neurohormone melatonin (MLT) may amplify IL-2 activity and reduce its dose required to activate the immune system. On this basis, we have compared the immune effects of presurgical therapy with high-dose IL-2 with respect to those obtained with preoperative neuroimmunotherapy consisting of low-dose IL-2 plus MLT. The study included 30 patients with gastrointestinal tract tumors, who were randomized to undergo surgery alone, or surgery plus a preoperative biotherapy with high-dose IL-2 (18 million IU/day subcutaneously for 3 days) or low-dose IL-2 (6 million IU/day subcutaneously for 5 days) plus MLT (40 mg/day orally). Patients underwent surgery within 36 hours from IL-2 interruption. Both IL-2 plus MLT were able to prevent surgery-induced lymphocytopenia. However, mean number of lymphocytes, T lymphocytes and T helper lymphocytes observed on day 1 of postoperative period was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. Moreover, toxicity was less in patients treated with IL-2 and MLT. This biological study shows that both immunotherapy with high-dose IL-2 or neuroimmunotherapy with low-dose IL-2 plus MLT preoperatively are tolerated biotherapies, capable of neutralizing surgery-induced lymphocytopenia in cancer patients. Moreover, the study would suggest that the neuroimmunotherapy may induce a more rapid effect on postoperative immune changes with respect to IL-2 alone.

Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10.

Lockwood K, Moesgaard S, Folkers K. Pharma Nord, Vejle, Denmark.

Biochem Biophys Res Commun. 1994 Mar 30;199(3):1504-8.

Relationships of nutrition and vitamins to the genesis and prevention of cancer are increasingly evident. In a clinical protocol, 32 patients having -"high-risk"- breast cancer were treated with antioxidants, fatty acids, and 90 mg. of CoQ10. Six of the 32 patients showed partial tumor regression. In one of these 6 cases, the dosage of CoQ10 was increased to 390 mg. In one month, the tumor was no longer palpable and in another month, mammography confirmed the absence of tumor. Encouraged, another case having a verified breast tumor, after non-radical surgery and with verified residual tumor in the tumor bed was then treated with 300 mg. CoQ10. After 3 months, the patient was in excellent clinical condition and there was no residual tumor tissue. The bioenergetic activity of CoQ10, expressed as hematological or immunological activity, may be the dominant but not the sole molecular mechanism causing the regression of breast cancer.

Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10.

Lockwood K, Moesgaard S, Hanioka T, Folkers K. Private Outpatient Clinic, Copenhagen, Denmark.

Mol Aspects Med. 1994;15 Suppl:s231-40.

Thirty-two typical patients with breast cancer, aged 32-81 years and classified 'high risk' because of tumor spread to the lymph nodes in the axilla, were studied for 18 months following an Adjuvant Nutritional Intervention in Cancer protocol (ANICA protocol). The nutritional protocol was added to the surgical and therapeutic treatment of breast cancer, as required by regulations in Denmark. The added treatment was a combination of nutritional antioxidants (Vitamin C: 2850 mg, Vitamin E: 2500 iu, beta-carotene 32.5 iu, selenium 387 micrograms plus secondary vitamins and minerals), essential fatty acids (1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and Coenzyme Q10 (90 mg per day). The ANICA protocol is based on the concept of testing the synergistic effect of those categories of nutritional supplements, including vitamin Q10, previously having shown deficiency and/or therapeutic value as single elements in diverse forms of cancer, as cancer may be synergistically related to diverse biochemical dysfunctions and vitamin deficiencies. Biochemical markers, clinical condition, tumor spread, quality of life parameters and survival were followed during the trial. Compliance was excellent. The main observations were: (1) none of the patients died during the study period. (the expected number was four.) (2) none of the patients showed signs of further distant metastases. (3) quality of life was improved (no weight loss, reduced use of pain killers). (4) six patients showed apparent partial remission.

Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases.

Lockwood K, Moesgaard S, Yamamoto T, Folkers K. Pharma Nord, Vejle, Denmark.

Biochem Biophys Res Commun. 1995 Jul 6;212(1):172-7.

Over 35 years, data and knowledge have internationally evolved from biochemical, biomedical and clinical research on vitamin Q10 (coenzyme Q10; CoQ10) and cancer, which led in 1993 to overt complete regression of the tumors in two cases of breast cancer. Continuing this research, three additional breast cancer patients also underwent a conventional protocol of therapy which included a daily oral dosage of 390 mg of vitamin Q10 (Bio-Quinone of Pharma Nord) during the complete trials over 3-5 years. The numerous metastases in the liver of a 44-year-old patient "disappeared," and no signs of metastases were found elsewhere. A 49-year-old patient, on a dosage of 390 mg of vitamin Q10, revealed no signs of tumor in the pleural cavity after six months, and her condition was excellent. A 75-year-old patient with carcinoma in one breast, after lumpectomy and 390 mg of CoQ10, showed no cancer in the tumor bed or metastases. Control blood levels of CoQ10 of 0.83-0.97 and of 0.62 micrograms/ml increased to 3.34-3.64 and to 3.77 micrograms/ml, respectively, on therapy with CoQ10 for patients A-MRH and EEL.

Regulation of the immune response by dehydroepiandrosterone and its metabolites

Loria R.M.; Padgett D.A.; Huynh P.N. Department of Microbiology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298-09678 USA

Journal of Endocrinology (United Kingdom), 1996, 150/Suppl. (S209-S220)

Dehydroepiandrosterone (5-androsten-3beta-ol-17-one, DHEA) has been shown to protect mice from a variety of lethal infections. This includes, but is not limited to, infection with viruses (herpes virus type 2, coxsackie virus B4 (CB4)), bacteria (Enterococcus faecalis, Pseudomonas aeruginosa), and a parasite (Cryptosporidium parvum). We have previously reported that androstenediol (5-androstene-3beta,17beta-diol, AED), derived from DHEA, is at least 100 x more effective in up-regulating systemic resistance against CB4 infection than its precursor. Furthermore, androstenetriol (5-androstene-3beta,7beta,17beta-triol, AET) which is formed by 7beta hydroxylation of AED, was more effective against CB4 infection than its precursor, AED. Neither steroid, however, has shown any significant direct antiviral effects. The in vitro influences of DHEA, AED and AET on a mitogen-induced mixed splenocyte proliferation assay were determined. The results showed that DHEA suppressed the proliferation of concanavalin A (ConA)- or lipopoly-saccharide-activated cultures in a dose-dependent manner. AED had little influence on the activation response. However, AET potentiated the response to both mitogens significantly above the control level. The regulation of interleukin (IL)-2 and IL-3 secretion from ConA-activated lymphocytes was analogous to these observations. These functions were depressed by DHEA, unaffected by AED, and potently increased by AET. Moreover, the classic immunosuppressive effects of hydrocortisone on ConA-induced lymphocyte proliferation, as well as IL-2 and IL-3 production, were unaffected by co-culture with DHEA and only minimally counteracted by AED. In contrast, AET significantly counteracted the effect of hydrocortisone when co-cultured together. These data show that while DHEA, AED and AET each function in a similar manner in vivo, in vitro their effects are dramatically different from one another with only AET potentiating the cellular response by increasing lymphocyte activation and counteracting the immunosuppressive activity of hydrocortisone.

The immunoneuroendocrine role of melatonin.

Maestroni GJ

J Pineal Res (Denmark) Jan 1993, 14 (1) p1-10

A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MIIO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as gamma-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.

Dairy proteins protect against dimethylhydrazine-induced intestinal cancers in rats.

McIntosh GH, Regester GO, Le Leu RK, Royle PJ, Smithers GW. CSIRO Division of Human Nutrition, Adelaide, South Australia.

J Nutr. 1995 Apr;125(4):809-16.

The impact of different dietary protein sources (whey, casein, soybean, red meat) on the incidence, burden and mass index of intestinal tumors induced by dimethylhydrazine in male Sprague-Dawley rats was assessed. A purified diet (based on AIN-76A) with a fat concentration of 20 g/100 g and other proteins substituted for casein (20 g/100 g) was used. Whey and casein diets were more protective against the development of intestinal tumors than were the red meat or soybean diets, as evidenced by a reduced incidence of rats affected (P = 0.15), fewer tumors per treatment group (burden, P < 0.005), and a reduced pooled area of tumors (tumor mass index) that formed (P = 0.39). Intracellular concentration of glutathione, an antioxidant and anticarcinogenic tripeptide, measured in liver, was greatest in whey protein- and casein-fed rats and lowest in soybean-fed animals (P < 0.001). For other tissues (spleen, colon, tumor) the differences were not significant, although the whey-fed animals had the highest concentrations of glutathione (P = 0.8). Whey is a source of precursors (cysteine-rich proteins) for glutathione synthesis and may be important in providing protection to the host by stimulating glutathione synthesis. A positive correlation was observed between mean fecal fat concentrations for rats in each treatment group and large intestinal tumor burden (r2 = 0.898, P = 0.05). Fecal fat could be involved in aiding initiation and/or promotion of carcinogenesis. Whatever the mechanism(s), dairy proteins, and whey proteins in particular, offer considerable protection to the host against dimethylhydrazine-induced tumors relative to the other protein sources examined.

Echinacea for preventing and treating the common cold.

Melchart D, Linde K, Fischer P, Kaesmayr J. Munchener Modell - Centre for Complementary Medicine Research, Technical University/Ludwig-Maximilians-University, Kaiserstr. 9, Munich, Germany, 80801. Muenchener.Modell@lrz.uni-muenchen.de

Cochrane Database Syst Rev. 2000;(2):CD000530.

BACKGROUND: Extracts of the plant Echinacea (family Compositae) are widely used in some European countries and the USA for upper respiratory tract infections. OBJECTIVES: The objective of this review was to assess the effects of preparations containing extracts of Echinacea in the prevention and treatment of the common cold. SEARCH STRATEGY: We searched the Cochrane Acute Respiratory Infections Group and Complementary Medicine Field's trials registers, MEDLINE, EMBASE, Phytodok and reference lists of articles. We also contacted researchers and manufacturers. Date of last search: Spring 1998. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing preparations containing an extract of Echinacea compared with a placebo, no treatment, or another treatment for common colds. DATA COLLECTION AND ANALYSIS: At least two independent reviewers assessed trial quality and extracted data. MAIN RESULTS: Sixteen trials (eight prevention trials, and eight trials on treatment of upper respiratory tract infections) with a total of 3396 participants were included. Variation in preparations investigated and methodological quality of trials precluded quantitative meta-analysis. Overall, the results suggested that some Echinacea preparations may be better than placebo. REVIEWER'S CONCLUSIONS: The majority of the available studies report positive results. However there is not enough evidence to recommend a specific Echinacea product, or Echinacea preparations for the treatment or prevention of common colds.

Vitamin E supplementation and in vivo immune response in healthy elderly subjects: A randomized controlled trial

Meydani S.N.; Meydani M.; Blumberg J.B.; Leka L.S.; Siber G.; Loszewski R.; Thompson C.; Pedrosa M.C.; Diamond R.D.; Stollar B.D. Dr. S.N. Meydani, Nutritional Immunology Laboratory, JM USDA HNRCA, Tufts University, 711 Washington St, Boston, MA 02111 USA

Journal of the American Medical Association (USA), 1997, 277/17 (1380-1386)

Objective. - To determine whether long-term supplementation with vitamin E enhances in vivo, clinically relevant measures of cell-mediated immunity in healthy elderly subjects.

Design. - Randomized, double-blind, placebo- controlled intervention study.

Setting and Participants. - A total of 88 free-living, healthy subjects at least 65 years of age. Intervention. - Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days.

Main Outcome Measures. - Delayed- type hypersensitivity skin response (DTH); antibody response to hepatitis B, tetanus and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin were assessed before and after supplementation.

Results. - Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3- fold, respectively), 60-mg/d (41% and 3-told, respectively), and 800-mg/d (49% and 2.5-fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (>48.4 micromol/L (2.08 mg/dL)) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed.

Conclusions. - Our results indicate that a level of vitamin E greater than currently recommended enhances certain clinically relevant in vivo indexes of T-cell-mediated function in healthy elderly persons. No adverse effects were observed with vitamin E supplementation.

Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients.

Micke P, Beeh KM, Schlaak JF, Buhl R. Pulmonary Division, III. Medical Department, Mainz University Hospital, D-455101 Mainz, Germany. p.micke@3-med.klinik.uni-mainz.de

Eur J Clin Invest. 2001 Feb;31(2):171-8.

HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. The semi-essential amino acid cysteine is the main source of the free sulfhydryl group of GSH and limits its synthesis. Therefore, different strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals. The aim of this study was to evaluate the effect of oral supplementation with two different cysteine-rich whey protein formulas on plasma GSH levels and parameters of oxidative stress and immune status in HIV-infected patients. In a prospective double blind clinical trial, 30 patients (25 male, 5 female; mean age (+/- SD) 42 +/- 9.8 years) with stable HIV infection (221 +/- 102 CD4 + lymphocytes L-1) were randomized to a supplemental diet with a daily dose of 45 g whey proteins of either Protectamin (Fresenius Kabi, Bad Hamburg, Germany) or Immunocal (Immunotec, Vandreuil, Canada) for two weeks. Plasma concentrations of total, reduced and oxidized GSH, superoxide anion (O2-) release by blood mononuclear cells, plasma levels of TNF-alpha and interleukins 2 and 12 were quantified with standard methods at baseline and after therapy. Pre-therapy, plasma GSH levels (Protectamin: 1.92 +/- 0.6 microM; Immunocal: 1.98 +/- 0.9 microM) were less than normal (2.64 +/- 0.7 microM, P = 0.03). Following two weeks of oral supplementation with whey proteins, plasma GSH levels increased in the Protectamin group by 44 +/- 56% (2.79 +/- 1.2 microM, P = 0.004) while the difference in the Immunocal group did not reach significance (+ 24.5 +/- 59%, 2.51 +/- 1.48 microM, P = 0.43). Spontaneous O2- release by blood mononuclear cells was stable (20.1 +/- 14.2 vs. 22.6 +/- 16.1 nmol h-1 10-6 cells, P = 0.52) whereas PMA-induced O2- release decreased in the Protectamin group (53.7 +/- 19 vs. 39.8 +/- 18 nmol h-1 10-6 cells, P = 0.04). Plasma concentrations of TNF-alpha and interleukins 2 and 12 (P > 0.08, all comparisons) as well as routine clinical parameters remained unchanged. Therapy was well tolerated. In glutathione-deficient patients with advanced HIV-infection, short-term oral supplementation with whey proteins increases plasma glutathione levels. A long-term clinical trial is clearly warranted to see if this "biochemical efficacy" of whey proteins translates into a more favourable course of the disease.

Immunostimulation of neutrophil phagocytic function by RU41740 (Biostim) in elderly subjects.

Minonzio F, Ongari AM, Palmieri R, Bochicchio D, Guidi G, Capsoni F. Istituto di Clinica Medica I, Universita di Milano.

Allergol Immunopathol (Madr). 1991 Mar-Apr;19(2):58-62.

On this randomized, double-blind trial we investigated the effect of RU41740, a glycoprotein extracted from Klebsiella pneumoniae, on human neutrophil function after oral administration to elderly subjects with a previously demonstrated phagocytic defect. Six subjects were given RU41740 orally at a daily dose of 2 mg for one week the first month and of 1 mg for one week the second month, while six subjects received placebo. Already after the first week of treatment with RU41740 (T1) and more evidently 3 weeks after the last administration of the first course of therapy (T2), a significant improvement of the neutrophil phagocytic capacity was observed; at the time T2, as well as at the end of the second course of therapy (T3), the phagocytic capacity was completely restored with no differences between control and aged subjects. Similar results were obtained in the chemiluminescence assays. As expected, placebo had no significant effect on neutrophil functions. No significant differences were observed between the two group of elderly subjects for total or differential leukocyte number. These results suggest that RU41740 exerts, almost in part, its clinical effect, i.e. the prevention of recurrent infections, by stimulating blood neutrophil phagocytic function.

Interaction of ascorbate and alpha-tocopherol.

Niki E.

Ann N Y Acad Sci. 1987;498:186-99.

Vitamins C and E function as water-soluble and lipid-soluble chain-breaking antioxidants, respectively, and protect lipids, proteins, and membranes from oxidative damage. Vitamin C scavenges oxygen radicals in the aqueous phase, whereas vitamin E scavenges oxygen radicals within the membranes. Vitamin C regenerates vitamin E by reducing vitamin E radicals formed when vitamin E scavenges the oxygen radicals. This interaction between vitamin C and vitamin E radicals can take place not only in homogeneous solutions but also in liposomal membrane systems where vitamins C and E reside separately outside and within the membranes respectively, and vitamin C can act as a synergist.

Contrasting effects of lactoferrin on human lymphocyte and monocyte natural killer activity and antibody-dependent cell-mediated cytotoxicity.

Nishiya K, Horwitz DA.

J Immunol. 1982 Dec;129(6):2519-23.

Iron and the iron-binding protein lactoferrin (LF) have significant effects on natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC). Human adherent and nonadherent blood mononuclear cells were incubated with K562 cells and antibody-sensitized Chang cells in short-term chromium-release assays. Ferric citrate (10(-3) M) inhibited both adherent and nonadherent NK cell activity, but had no effect upon ADCC. LF markedly affected adherent monocyte cytotoxicity, but had no effect on nonadherent lymphocytes. LF enhanced NK in a dose-dependent manner, but similar concentrations paradoxically inhibited ADCC. LF acted directly upon the adherent effector cell because pretreatment of cells for 30 min was sufficient for enhancement. Fe-saturated LF as well as the unsaturated protein enhanced adherent cell NK. Transferrin in all concentrations tested did not alter NK activity. These studies show inhibitory effects of iron on immune function in addition to those previously described and reveal a new regulatory role for LF. The selective effect of LF on adherent cells provides further evidence that monocytes, at least in the adherent state, can have potent NK activity. The opposite effects of LF on NK and ADCC are unexplained and may serve as a probe to define the mechanisms involved.

Self-regulation of salivary immunoglobulin A by children.

Olness K, Culbert T, Uden D. Minneapolis Children's Medical Center.

Pediatrics. 1989 Jan;83(1):66-71.

In a prospective randomized controlled study, the possibility that children could regulate their own salivary immunoglobulins was investigated using cyberphysiologic techniques. Fifty-seven children were randomly assigned to one of three groups. Group A subjects learned self-hypnosis with permission to increase immune substances in saliva as they chose; group B subjects learned self-hypnosis with specific suggestions for control of saliva immunoglobulins; group C subjects were given no instructions but received equal attention time. At the first visit, saliva samples (baseline) were collected, and each child looked at a videotape concerning the immune system and was tested with the Stanford Children's Hypnotic Susceptibility Scale. At the second visit, an initial saliva sample was collected prior to 30 minutes of self-hypnosis practice or conversation. At the conclusion of the experiment, a third saliva sample was obtained. Salivary IgA and IgG levels for all groups were stable from the first to the second sampling. Children in group B demonstrated a significant increase in IgA (P less than .01) during the experimental period. There were no significant changes in IgG. Stanford Children's Hypnotic Susceptibility Scale scores were stable across groups and did not relate to immunoglobulin changes.

Lipopolysaccharide-induced enhancement of natural killer cell cytotoxicity: Comparison of rats fed menhaden, safflower and essential fatty acid deficient diets

Penturf M.E.; McGlone J.J.; Griswold J.A. USA

Journal of Nutritional Immunology (USA), 1997, 5/2 (47-56)

The n-6 and n-3 families of fatty acids serve as precursors in the formation of mediators observed in inflammation. Eicosanoids from the cyclooxygenase and lipoxygenase pathways have been shown to influence natural killer (NK ) cell activity . In this study, rats were fed diets either deficient in essential fatty acids (EFAD), or diets that contained marine oil (15% menhaden, MEN) or safflower oil (15% safflower, SAF). Rats were then subjected to either in vivo lipopolysaccaride (LPS) or a sham procedure. LPS treated animals had higher (p < 0.05) NK activity than those of the sham group. EFAD-fed animals had higher (p < 0.05) NK activity than animals fed diets containing lipids. Dietary treatment and LPS interactions were not significant, indicating that major shifts in cell lipid concentrations did not alter endotoxin-induced enhancement of NK activity. Rats fed EFAD diets had enhanced NK activity in both sham and LPS-treated animals.

Use of echinacea in medicine.

Percival SS. Food Science and Human Nutrition Department, The University of Florida, Gainesville, FL 32611, USA. ssp@gnv.ifas.ufl.edu

Biochem Pharmacol. 2000 Jul 15;60(2):155-8.

Echinacea, also known as the purple coneflower, is an herbal medicine that has been used for centuries, customarily as a treatment for the common cold, coughs, bronchitis, upper respiratory infections, and some inflammatory conditions. Research on echinacea, including clinical trials, is limited and largely in German. More information is needed before a definitive statement about the efficacy of echinacea can be made. Future work needs to clearly identify the species of echinacea and distinguish between the efficacy of the different plant parts (roots versus upper plant parts). Although many of the active compounds of echinacea have been identified, the mechanism of action is not known, nor is the bioavailability, relative potency, or synergistic effects of the active compounds known. Interpretation of existing literature suggests that echinacea should be used as a treatment for illness, not as a means for prevention of illness. The consensus of the studies reviewed in this article is that echinacea is indeed effective in reducing the duration and severity of symptoms, but that this effect is noted only with certain preparations of echinacea. Studies show that the plant and its active components affect the phagocytic immune system, but not the specifically acquired immune system.

Systemic augmentation of the immune response in mice by feeding fermented milks with Lactobacillus casei and Lactobacillus acidophilus.

Perdigon G, de Macias ME, Alvarez S, Oliver G, de Ruiz Holgado AP. Centro de Referencia para Lactobacilos (CERELA), Chacabuco, Tucuman, Argentina.

Immunology 1988 Jan;63(1):17-23

This study investigates the effect of feeding fermented milks with Lactobacillus casei, Lactobacillus acidophilus and a mixture of both micro-organisms on the specific and non-specific host defence mechanisms in Swiss mice. Animals fed with fermented milk for 8 days (100 micrograms/day) showed an increase in both phagocytic and lymphocytic activity. This activation of the immune system began on the 3rd day, reached a maximum on the 5th, and decreased slightly on the 8th day of feeding. In the 8-day treated mice, boosted with a single dose (100 micrograms) on the 11th day, the immune response increased further. The feeding with fermented milk produced neither hepatomegaly nor splenomegaly. These results suggest that L. casei and L. acidophilus, associated with intestinal mucosae, can influence the level of activation of the immune system. The possible clinical application of fermented milks as immunopotentiators is also discussed.

Molecules of Emotion: Why You Feel the Way You Feel 1999.

Pert, C.B.

New York: Simon &amp; Schuster.

Effects of zinc deficiency on Th1 and Th2 cytokine shifts.

Prasad AS. Wayne State University, University Health Center, Detroit, MI 48201, USA. prasada@karmanos.org

J Infect Dis. 2000 Sep;182 Suppl 1:S62-8.

Nutritional deficiency of zinc is widespread throughout developing countries, and zinc-deficient persons have increased susceptibility to a variety of pathogens. Zinc deficiency in an experimental human model caused an imbalance between Th1 and Th2 functions. Production of interferon-gamma and interleukin (IL)-2 (products of Th1) were decreased, whereas production of IL-4, IL-6, and IL-10 (products of Th2) were not affected during zinc deficiency. Zinc deficiency decreased natural killer cell lytic activity and percentage of precursors of cytolytic T cells. In HuT-78, a Th0 cell line, zinc deficiency decreased gene expression of thymidine kinase, delayed cell cycle, and decreased cell growth. Gene expression of IL-2 and IL-2 receptors (both alpha and beta) and binding of NF-kappaB to DNA were decreased by zinc deficiency in HuT-78. Decreased production of IL-2 in zinc deficiency may be due to decreased activation of NF-kappaB and subsequent decreased gene expression of IL-2 and IL-2 receptors.

Zinc deficiency: changes in cytokine production and T-cell subpopulations in patients with head and neck cancer and in noncancer subjects.

Prasad AS; Beck FW; Grabowski SM; Kaplan J; Mathog RH Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI

Proc Assoc Am Physicians Jan 1997, 109 (1) p68-77

Cell-mediated immune dysfunctions and susceptibility to infections have been observed in zinc -deficient human subjects. In this study, we investigated the production of cytokines and characterized the T-cell subpopulations in three groups of mildly zinc -deficient subjects. These included head and neck cancer patients, healthy volunteers who were found to have a dietary deficiency of zinc, and healthy volunteers in whom we induced zinc deficiency experimentally by dietary means. We used cellular zinc criteria for the diagnosis of zinc deficiency. We assayed enzyme-linked immunosorbent assay the production of cytokines from phytohemagglutinin-stimulated peripheral blood mononuclear cells and assessed by flow cytometry the differences in T-cell subpopulations. Our studies showed that the cytokines produced by TH1 cells were particularly sensitive to zinc status, inasmuch as the production of interleukin-2 (IL-2) and interferon-gamma were decreased even though the deficiency of zinc was mild in our subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not affected by zinc deficiency. Natural killer cell lytic activity also was decreased in zinc -deficient subjects. Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+ CD11b-, precursors of cytolytic T cells, were decreased in mildly zinc -deficient subjects. An imbalance between the functions of TH1 and TH2 cells and changes in T-cell subpopulations are most probably responsible for cell-mediated immune dysfunctions in zinc deficiency.

Vitamin B6 and immune competence.

Rall LC, Meydani SN. Nutritional Immunology Laboratory, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111.

Nutr Rev 1993 Aug;51(8):217-25

Animal and human studies suggest that vitamin B6 deficiency affects both humoral and cell-mediated immune responses. Lymphocyte differentiation and maturation are altered by deficiency, delayed-type hypersensitivity responses are reduced, and antibody production may be indirectly impaired. Although repletion of the vitamin restores these functions, megadoses do not produce benefits beyond those observed with moderate supplementation. Additional human studies indicate that vitamin B6 status may influence tumor growth and disease processes. Deficiency of the vitamin has been associated with immunological changes observed in the elderly, persons infected with human immunodeficiency virus (HIV), and those with uremia or rheumatoid arthritis. Future research efforts should focus on establishing the mechanism underlying the effects of vitamin B6 on immunity and should attempt to establish safe intake levels that optimize immune response.

Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged >/=90 y.

Ravaglia G, Forti P, Maioli F, Bastagli L, Facchini A, Mariani E, Savarino L, Sassi S, Cucinotta D, Lenaz G. Department of Internal Medicine, Cardioangiology, and Hepatology, the Department of Angiology and Blood Coagulation, and the Division of Geriatric Medicine, University Hospital Sant'Orsola-Malpighi, Bologna, Italy. ravaglia@almadns.unibo.it

Am J Clin Nutr. 2000 Feb;71(2):590-8.

BACKGROUND: Natural killer (NK) cells play a role in natural immunity against tumor and infected cells. Advanced aging is associated with functional impairment of NK cells and increased susceptibility to nutritional deficiencies.

OBJECTIVE: Our objective was to test whether micronutrient status affects NK cell activity in an older population. DESIGN: The relations between NK cell variables (percentage of leukocytes and cytotoxicity) and blood concentrations of selected micronutrients were studied in 62 healthy, free-living northern Italian subjects (25 men, 37 women) aged 90-106 y. Anthropometric measurements were also made.

RESULTS: All subjects were well nourished according to age-specific anthropometric norms but many of them had micronutrient deficiencies. The prevalence of micronutrient deficiency was highest for selenium (in approximately 50% of both sexes), zinc (in 52% of men and 41% of women), and vitamin B-6 (in 40% of men and 59% of women), followed by vitamin A (in 16% of men and 27% of women) and vitamin E, vitamin B-12, and folate (each in <10% of both sexes). Ubiquinone-10 status was inadequate in 40% of women and 24% of men (P = 0.02). The percentage of NK cells was associated with serum zinc (men: r = 0.573, P = 0. 007; women: r = 0.373, P = 0.031) and selenium (women: r = 0.409, P = 0.018) concentrations. In women only, NK cell cytotoxicity at different effector-target cell ratios was positively associated with plasma vitamin E and ubiquinone-10 concentrations (P < 0.05). No significant associations with NK cell variables were found for the other measured nutrients.

CONCLUSIONS: The results of this study strengthen the hypothesis that individual micronutrients may affect the number and function of NK cells in old age. The study also confirms the high prevalence of micronutrient deficiencies in healthy and apparently well-nourished persons aged >/=90 y.

Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation

Santos M.S.; Meydani S.N.; Leka L.; Wu D.; Fotouhi N.; Meydani M.; Hennekens C.H.; Gaziano J.M. Nutritional Immunology Laboratory, Jean Mayer USDA HNRCA, Tufts University, 711 Washington Street, Boston, MA 02111 USA

American Journal of Clinical Nutrition (USA), 1996, 64/5 (772-777)

Natural killer (NK) cell activity has been postulated to be an immunologic link between beta-carotene and cancer prevention. In a cross- sectional, placebo-controlled, double-blind study we examined the effect of 10-12 y of beta-carotene supplementation (50 mg on alternate days) on NK cell activity in 59 (38 middle-aged men, 51-64 y; 21 elderly men, 65-86 y) Boston area participants in the Physicians' Health Study. No significant difference was seen in NK cell activity due to beta-carotene supplementation in the middle-aged group. The elderly men had significantly lower NK cell activity than the middle-aged men; however, there was no age-associated difference in NK cell activity in men supplemented with beta-carotene. beta-carotene- supplemented elderly men had significantly greater NK cell activity than elderly men receiving placebo. The reason for this is unknown; however, it was not due to an increase in the percentage of NK cells, nor to an increase in interleukin 2 (IL-2) receptor expression, nor to IL-2 production. beta- carotene may be acting directly on one or more of the lytic stages of NK cell cytotoxicity, or on NK cell activity-enhancing cytokines other than IL-2, such as IL-12. Our results show that long-term beta-carotene supplementation enhances NK cell activity in elderly men, which may be beneficial for viral and tumoral surveillance.

Mechanism for the antitumor and anticachectic effects of n-3 fatty acids.

Sauer LA, Dauchy RT, Blask DE. Bassett Research Institute, Cooperstown, New York 13326, USA. lensauer@juno.com

Cancer Res. 2000 Sep 15;60(18):5289-95.

Dietary intake of the n-6 fatty acid (FA) linoleic acid (LA) has a strong growth-promoting effect on many rodent tumors and human tumor xenografts grown in immunodeficient rodents. n-3 FAs such as alpha-linolenic and eicosapentaenoic acids (EPAs), which differ from LA and arachidonic acid, respectively, by only a single double bond in the n-3 position, are recognized cancer chemopreventive and anticachectic agents. Understanding how this seemingly small structural difference leads to such remarkable functional differences has been a challenge. In a previous study, we showed that LA uptake, [3H]thymidine incorporation into DNA, and total DNA content were decreased in tissue-isolated hepatoma 7288CTC perfused in situ with arterial blood containing alpha-linolenic acid, EPA, or docosahexaenoic acids. The Ki for the inhibition of LA uptake and [3H]thymidine incorporation by alpha-linolenic acid was 0.18 and 0.25 mM, respectively. Here we show that the addition of alpha-linolenic acid or EPA to arterial blood inhibits tumor FA uptake, including LA, and the subsequent conversion of LA to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) in vivo and during perfusion in situ. [3H]Thymidine incorporation during perfusion in situ was also inhibited. Addition of 13-HODE to the arterial blood reversed the inhibition of [3H]thymidine incorporation but had no effect on FA uptake. These two n-3 FAs also inhibited FA transport in inguinal fat pads in vivo and during perfusion in situ in fed (FA uptake) and fasted (FA release) rats. The effects of EPA and talinolenic acid on transport of saturated, monounsaturated, and n-6 polyunsaturated FAs in hepatoma 7288CTC and inguinal fat pads during perfusion in situ were reversed by the addition of forskolin (1 microM), pertussis toxin (0.5 microg/ml), or 8-bromo-cyclic AMP (10 microM) to the arterial blood. We conclude that the antitumor and anticachectic effects of n-3 FAs on hepatoma 7288CTC and inguinal fat pads in vivo result from an inhibition of FA transport. These inhibitions are mediated by a putative n-3 FA receptor via a Gi protein-coupled signal transduction pathway that decreases intracellular cyclic AMP. A specific decrease in LA uptake and its conversion to the mitogen 13-HODE causes the tumor growth inhibition.

Zinc deficiency impairs immune responses against parasitic nematode infections at intestinal and systemic sites.

Scott ME, Koski KG. Institute of Parasitology, School of Dietetics and Human Nutrition, McGill University, Macdonald Campus, Ste-Anne de Bellevue, Quebec H9X 3V9, Canada.

J Nutr. 2000 May;130(5S Suppl):1412S-20S.

Research on the complex interactions among host nutritional status, parasitic infection and immune responsiveness has focused on the detrimental consequences of parasitic infections on host nutritional status and on mechanisms by which malnutrition impairs immunocompetence. Curiously, relatively few studies have examined the effects of malnutrition on the immune response in the parasite-infected host, and even fewer have considered the events occurring at the intestinal level, where absorption of nutrients occurs, intestinal parasites reside, and the gastrointestinal-associated lymphoid tissues play a role in directing both the local and the more systemic immune responses. Our work using a zinc-deficient nematode-infected mouse model reveals that parasites are better able to survive in the zinc-deficient hosts than in well-nourished hosts; that the production of interleukin-4 in the spleen of zinc-deficient mice is depressed, leading to depressed levels of IgE, IgG(1) and eosinophils; and that the function of T cells and antigen-presenting cells is impaired by zinc deficiency as well as by energy restriction. Given the paramount role of the gastrointestinal-associated lymphoid tissues in inducing and regulating immune responses to intestinal parasites and in orchestrating responses in the spleen and peripheral circulation, we conclude that zinc deficiency (in association with energy restriction) exerts profound effects on the gut mucosal immune system, leading to changes in systemically disseminated immune responses and, importantly, to prolonged parasite survival.

Synergism of nutrition, infection, and immunity: an overview.

Scrimshaw NS, SanGiovanni JP. Food and Nutrition Programme for Human and Social Development, United Nations University (Program Office), Boston, MA 02114-0500, USA. Scrimshaw@inf.unu.edu

Am J Clin Nutr 1997 Aug;66(2):464S-477S

Infections, no matter how mild, have adverse effects on nutritional status. The significance of these effects depends on the previous nutritional status of the individual, the nature and duration of the infection, and the diet during the recovery period. Conversely, almost any nutrient deficiency, if sufficiently severe, will impair resistance to infection. Iron deficiency and protein-energy malnutrition, both highly prevalent, have the greatest public health importance in this regard. Remarkable advances in immunology of recent decades have increased insights into the mechanisms responsible for the effects of infection. These include impaired antibody formation; loss of delayed cutaneous hypersensitivity; reduced immunoglobulin concentrations; decreased thymic and splenic lymphocytes; reduced complement formation, secretory immunoglobulin A, and interferon; and lower T cells and T cells subsets (helper, suppressor-cytotoxic, and natural killer cells) and interleukin 2 receptors. The effects observed with single or multiple nutrient deficiencies are due to some combination of these responses. In general, cell-mediated and nonspecific immunity are more sensitive than humoral immunity.

Zinc and immune function: the biological basis of altered resistance to infection.

Shankar AH; Prasad AS Department of International Health, The Johns Hopkins University School of Public Health, Baltimore, MD 21205, USA. ashankar@jhsph.edu

Am J Clin Nutr Aug 1998, 68 (2 Suppl) p447S-463S

Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation. (271Refs.)

Aging, exercise, training, and the immune system.

Shinkai S; Konishi M; Shephard RJ Department of Public Health, Ehime University School of Medicine, Japan.

Exerc Immunol Rev 1997, 3 p68-95

Human immune function undergoes adverse changes with aging, including development of a relative immune deficiency and an immune dysregulated state. The T cells show the largest age-related differences in distribution and function. The antibody production capacity of B cells also shows an age-related decline. Acute bouts of exercise modulate many immune parameters as seen in peripheral blood. With regard to NK cell activity, a single bout of moderate exercise seems to be well tolerated by the elderly, and the resting NK cell activity of elderly subjects seems to increase with training. Cross-sectional comparisons of immune status imply that habitual physical activity may enhance NK cell activity and check certain aspects of the age-related decline in T cell function. Future studies are required to clarify whether such long-term exercise and resulting improvements of immune function give rise to any beneficial effects on infections, malignancies, and autoimmune disorders. (162 Refs.)

Dehydroepiandrosterone sulfate decreases the interleukin-2-mediated overactivity of the natural killer cell compartment in senile dementia of the Alzheimer type

Solerte S.B.; Fioravanti M.; Schifino N.; Cuzzoni G.; Fontana I.; Vignati G.; Govoni S.; Ferrari E. Dr. S.B. Solerte, Department of Internal Medicine, University of Pavia, Ospedale S. Margherita, Piazza Borromeo 2, I-27100 Pavia Italy

Dementia and Geriatric Cognitive Disorders (Switzerland), 1999, 10/1 (21-27)

Since dehydroepiandrosterone sulfate (DHEAS) has been involved in the regulation of cellular immunity, the aim of the presence study was to evaluate whether the age-dependent reduction of DHEAS was associated with changes of natural killer (NK) immune function in healthy elderly subjects and in patients with senile dementia of the Alzheimer type (SDAT). Circulating DHEAS was determined throughout 24 h (circadian profile). NK cytotoxic activity was measured as spontaneous and induced cytotoxicity during exposure with DHEAS (10-7 M), interleukin-2 (IL-2; 100 IU) and IL-2 (100 IU) coincubated with DHEAS (10-7 M). DHEAS was significantly reduced in healthy subjects (mesor M plus or minus SD = 2.3 plus or minus 0.5 micromol/l) and SDAT (1.6 plus or minus 0.4 micromol/l) patients compared to healthy young subjects (6.7 plus or minus 0.9 micromol/l; p < 0.001); significant differences were also found when healthy elderly subjects and SDAT patients were compared (p < 0.01). A significant inverse correlation between age and DHEAS levels was demonstrated in SDAT and healthy elderly subjects (p < 0.05). The decrease in 24-hour DHEAS secretion was associated with a higher NK cytotoxic response to DHEAS in the healthy elderly subject group than in healthy subjects of young age (p < 0.01). Increased NK cell activity during IL-2 incubation was found in patients with SDAT in comparison with the healthy elderly subject (p < 0.001). On the contrary, NK cell cytotoxic response of SDAT patients was less pronounced during DHEAS exposure and when DHEAS was coincubated with IL-2 (p < 0.001). These data suggest an immunomodulatory role of DHEAS on NK functional activity in physiological aging and SDAT. The antagonizing effect of DHEAS on NK overactivity during exposure with cytokines might counteract some neuroimmune components related to the pathogenesis and progression of the disease.

Effect of psychosocial treatment on survival of patients with metastatic breast cancer.

Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California.

Lancet. 1989 Oct 14;2(8668):888-91.

The effect of psychosocial intervention on time of survival of 86 patients with metastatic breast cancer was studied prospectively. The 1 year intervention consisted of weekly supportive group therapy with self-hypnosis for pain. Both the treatment (n = 50) and control groups (n = 36) had routine oncological care. At 10 year follow-up, only 3 of the patients were alive, and death records were obtained for the other 83. Survival from time of randomisation and onset of intervention was a mean 36.6 (SD 37.6) months in the intervention group compared with 18.9 (10.8) months in the control group, a significant difference. Survival plots indicated that divergence in survival began at 20 months after entry, or 8 months after intervention ended.

Antioxidant defense: vitamins E and C and carotenoids.

Stahl W, Sies H. Institut fur Physiologische Chemie I, Heinrich-Heine-Universitat Dusseldorf, Germany.

Diabetes. 1997 Sep;46 Suppl 2:S14-8.

Reactive oxygen species are thought to be implicated in the pathogenesis of various human diseases. They are generated endogenously under physiological and pathological conditions but also upon exposure to exogenous challenge. The organism maintains defense systems against reactive oxygen species, including enzymes and low-molecular-weight antioxidants. Important antioxidants such as vitamins E and C and carotenoids are provided from the diet. Vitamin E, as the major chain-breaking antioxidant, inhibits lipid peroxidation, thus preventing membrane damage and modification of low-density lipoproteins. It is regenerated by the water-soluble vitamin C. Carotenoids efficiently scavenge singlet molecular oxygen and peroxyl radicals. There is increasing evidence from epidemiological studies, animal experiments, and in vitro investigations that an increased intake of antioxidants is associated with a diminished risk for several diseases.

Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months.

van Vollenhoven RF; Morabito LM; Engleman EG; McGuire JL Division of Immunology and Rheumatology, Stanford University Medical Center, CA 94305-5111, USA.

J Rheumatol, 1998 Feb, 25:2, 285-9

OBJECTIVE: To determine whether longterm therapy (up to 1 year) with the weakly androgenic adrenal steroid dehydroepiandrosterone (DHEA) is feasible and beneficial in patients with mild to moderate systemic lupus erythematosus (SLE).

METHODS: In a prospective, open label, uncontrolled longitudinal study 50 female patients (37 premenopausal, 13 postmenopausal) with mild to moderate SLE were treated with oral DHEA 50-200 mg/day.

RESULTS: DHEA therapy was associated with increases in the serum levels of DHEA, DHEA sulfate, and testosterone and, for those patients who continued DHEA, with decreasing disease activity measured by SLE Disease Activity Index score (p < 0.01), patient global assessment (p < 0.01), and physician global assessment (p < 0.05), compared to baseline. Concurrent prednisone doses were reduced (p < 0.05). These improvements were sustained over the entire treatment period. Thirty-four patients (68%) completed 6 months of treatment and 21 patients (42%) completed 12 months. Mild acneiform dermatitis was the most common adverse event (54%). Pre and postmenopausal women experienced similar efficacy and adverse effects from DHEA.

CONCLUSION: DHEA was well tolerated and appeared clinically beneficial, with the benefits sustained for at least one year in those patients who maintained therapy.

Influence of level of dietary lipids and exercise on immune status in athletes.

Venkatraman, J.T., Rowland, J.A., Denardin, E., Horvath, P.J., Pendergast, D.R.

FASEB J. 1996; 10(3): A556.

No abstract available.

[Double-blind study of an immunomodulator of bacterial origin (Biostim) in the prevention of infectious episodes in chronic bronchitis] [Article in French]

Viallat JR, Costantini D, Boutin C, Farisse P.

Poumon Coeur. 1983 Jan-Feb;39(1):53-7.

A double-blind trial was conducted to evaluate the capacity of an immunomodulator of bacterial origin (Biostim) to diminish the frequency of infectious episodes in chronic bronchitis. The study duration was 9 months, Biostim being administered orally initially, with follow-up examinations after 2 and 4 months. Of the 73 subjects selected, 38 received Biostim and 35 a placebo (no significant differences between the two groups). By the 9th month, the duration in days of infectious episodes and of antibiotic therapy was 13 +/- 1.3 and 11.5 +/- 1.4 days respectively for the group receiving Biostim, and 33 +/- 5.8 and 41 +/- 9.5 respectively for the placebo group (p less than 0.05). No signs of intolerance and particularly no immunotoxicity were observed: absence of elevation of IgE or anti-Biostim antibody titres. Pre-winter administration of Biostim to subjects at high risk would appear to significantly diminish the frequency of infectious episodes and thus the consumption of antibiotics.

Vitamin A supplementation: implications for morbidity and mortality in children.

Villamor E, Fawzi WW. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

J Infect Dis. 2000 Sep;182 Suppl 1:S122-33.

Vitamin A deficiency impairs epithelial integrity and systemic immunity and increases the incidence and severity of infections during childhood. However, findings from vitamin A supplementation trials are not consistent. Supplementation has resulted in significant reductions in mortality in several (but not all) large community-based trials among apparently healthy children. In hospital-based studies, vitamin A supplements have been consistently found to reduce the severity of measles infection, but no effect on nonmeasles respiratory infections has been observed. In some cases, the supplements were associated with an apparently increased risk of lower respiratory infection. Vitamin A supplements also reduced the severity of diarrhea in most (but not all) trials. Potential explanations for the differences in efficacy across trials are reviewed. While vitamin A supplementation is effective in reducing total mortality and complications from measles infections, it is likely to be more effective in populations suffering from nutritional deficiencies.

The therapeutic effect of bovine lactoferrin in the host infected with Helicobacter pylori.

Wada T, Aiba Y, Shimizu K, Takagi A, Miwa T, Koga Y. Dept. of Infectious Diseases, Tokai University School of Medicine, Kanagawa, Japan.

Scand J Gastroenterol 1999 Mar;34(3):238-43

BACKGROUND: It remains unclarified whether bovine lactoferrin (bLF) can exert a therapeutic effect on the host infected with Helicobacter pylori.

METHODS: Germfree BALB/c mice were orally inoculated with H. pylori to induce infection. Three weeks after infection the mice were given bLF orally once daily for 2 or 4 weeks and were then killed to examine the bacterial number in the stomach and the serum antibody titer to H. pylori. To count the number of epithelium-bound H. pylori, the resected stomach was agitated in phosphate-buffered saline to remove non-bound H. pylori before bacterial enumeration.

RESULTS: The administration of 10 mg bLF for 3 to 4 weeks decreased the number of H. pylori in the stomach to one-tenth and also exerted a significant inhibitory effect on the attachment of H. pylori to the stomach. As a result, the serum antibody titer to H. pylori, whose level is presumed to represent the size of the immune response by the host, thereby reflecting the degree of bacterial attack, decreased to an undetectable level.

CONCLUSIONS: These findings suggest that bLF exerts an inhibitory effect on colonizing H. pylori by detaching the bacterium from the gastric epithelium and by exerting a direct anti-bacterial effect.

Pace GW; Leaf CD
Research Triangle Pharmaceuticals, Durham, NC, USA.
Free Radic Biol Med Oct 1995, 19 (4) p523-8

Evidence has accumulated suggesting that HIV-infected patients are under chronic oxidative stress. Perturbations to the antioxidant defense system, including changes in levels of ascorbic acid, tocopherols, carotenoids, selenium, superoxide dismutase, and glutathione, have been observed in various tissues of these patients. Elevated serum levels of hydroperoxides and malondialdehyde also have been noted and are indicative of oxidative stress during HIV infection. Indications of oxidative stress are observed in asymptomatic HIV-infected patients early in the course of the disease. Oxidative stress may contribute to several aspects of HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss, and increased sensitivity to drug toxicities. Glutathione may play a role in these processes, and thus, agents that replete glutathione may offer a promising treatment for HIV-infected patients. Clinical studies are underway to evaluate the efficacy of the glutathione-repleting agents, L-2-oxothiazolidine-4-carboxy lic acid (OTC) and N-acetylcysteine (NAC), in HIV-infected patients. (93 Refs.)

Demling RH; DeBiasse MA
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Crit Care Clin Jul 1995, 11 (3) p651-73
[published erratum appears in Crit Care Clin 1996 Oct;12(4):xi]

Micronutrients play a key role in many of the metabolic processes that promote survival from critical illness. For vitamins, these processes include oxidative phosphorylation, which is altered in the patient with systemic inflammation, and protection against mediators, in particular oxidants. Trace elements are essential for direct antioxidant activity as well as functioning as cofactors for a variety of antioxidant enzymes. Wound healing and immune function also depend on adequate levels of vitamins and trace elements (Table 6). Of extreme importance is the ease with which a deficiency state can develop in the critically ill because of decreased nutrient intakes and increased requirements. Daily intakes up to or exceeding many times the RDA usually are required. The enteral route is preferred, although, if not available, most of these agents can be given by the parenteral route. In that case, however, dose recommendations are less clear. Attention to micronutrients is paramount both in optimizing the nutritional management of the critically ill and in the overall management of these patients. It also is essential in promoting positive outcomes and decreasing complications. (40 Refs.)

Dubbels R; Reiter RJ; Klenke E; Goebel A; Schnakenberg E; Ehlers C; Schiwara HW; Schloot W
Center of Human Genetics and Genetic Counselling, University of Bremen, Germany.
J Pineal Res (Denmark) Jan 1995, 18 (1) p28-31

Melatonin, the chief hormone of the pineal gland in vertebrates, is widely distributed in the animal kingdom. Among many functions, melatonin synchronizes circadian and circannual rhythms, stimulates immune function, may increase life span, inhibits growth of cancer cells in vitro and cancer progression and promotion in vivo, and was recently shown to be a potent hydroxyl radical scavenger and antioxidant . Hydroxyl radicals are highly toxic by-products of oxygen metabolism that damage cellular DNA and other macromolecules. Herein we report that melatonin, in varying concentrations, is also found in a variety of plants. Melatonin concentrations, measured in nine different plants by radioimmunoassay, ranged from 0 to 862 pg melatonin/mg protein. The presence of melatonin was verified by gas chromatography/mass spectrometry. Our findings suggest that the consumption of plant materials that contain high levels of melatonin could alter blood melatonin levels of the indole as well as provide protection of macromolecules against oxidative damage.

Singh A; Failla ML; Deuster PA
Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
J Appl Physiol Jun 1994, 76 (6) p2298-303

To examine the effect of zinc (Zn) supplementation on exercise-induced changes in immune function, five male runners were randomly assigned in a double-blind crossover design to take a supplement (S; 25 mg of Zn and 1.5 mg of copper) or placebo (P) twice daily for 6 days. On morning 4 of each phase, 1 h after taking S or P, subjects ran on a treadmill at 70-75% of maximal oxygen uptake until exhaustion (approximately 2 h). Blood samples were obtained before (Pre), immediately after (Post), and 1 (Rec1) and 2 (Rec2) days after the run. [3H]thymidine incorporation by mitogen-treated mononuclear cell cultures was significantly lower (P < 0.05) Post than Pre, Rec1, or Rec2 for both S and P. Respiratory burst activity of isolated neutrophils was enhanced after exercise with P but not with S (P: Pre 12.0 +/- 1.1 vs. Post 17.6 +/- 2.3 nmol O2-/10(6) cells; S: Pre 11.7 +/- 0.3 vs. Post 12.1 +/- 1.2 nmol O2-/10(6) cells). Thus supplemental Zn blocked the exercise-induced increase in reactive oxygen species. Whether this antioxidant effect of Zn will benefit individuals exposed to chronic physical stress remains to be determined.

Fernandes G
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7874.
Clin Immunol Immunopathol Aug 1994, 72 (2) p193-7

In summary, it is well established that moderate calorie restriction or reduction in overall high calorie food intake prevents or forestalls the development of age-associated disease incidence such as breast cancer and renal disease in rodents. A similar approach could also readily be applied in humans for preventing the risk and rise of life-shortening diseases. Many age-associated diseases, particularly autoimmune diseases with viral etiology, appear to be exacerbated in the presence of adverse lipid intake such as an increased level of vegetable oils or trans-fatty acids from the usage of hydrogenated dietary oils. At present, nearly 35-40% of the total calories are from dietary fats and/or of lipid origin. Although usage of saturated fat, which increases cardiovascular disease, has been reduced to a large extent in the United States, consumption of both monounsaturated and polyunsaturated fats of omega-6 origin has either increased or simply been substituted in place of saturated fats. Further, for the past 50 years, a significant reduction in highly polyunsaturated fat consumption such as marine oil has also occurred specifically in the United States. The reduction in omega-3 lipids of marine or vegetable source occurs primarily because of short shelf life due to rancidity. However, the increased consumption of omega-6 or a vegetable source of oils and decreased omega-3 intake may increase in vivo the production of free radicals and higher proinflammatory cytokines. Our ongoing studies reveal that proinflammatory vegetable oil could increase autoimmune disease by increasing the free radical formation by decreasing the antioxidant enzyme mRNA levels, thereby further decreasing immune function, particularly the production of anti-inflammatory cytokines such as IL-2 and TGF beta mRNA levels. In contrast, omega-3 lipid intake in the presence of an antioxidant supplement appears to exert protection against autoimmunity by enhancing antioxidant enzymes and TGF beta mRNA levels and by preventing the rise in oncogene expression. However, detailed studies are required to establish the protective and deleterious role of different commonly consumed lipids or dietary oils by the general population, particularly during middle and aging years. Further, we also propose that combining nonsteroidal drug therapy along with moderate calorie reduction in the presence of more protective omega-3 dietary lipids of either marine or vegetable source and decreasing the levels of mono- and polyunsaturated lipids may provide additional protection against the age-associated rise in malignancy and autoimmune disorders. (43 Refs.)

Flescher E; Ledbetter JA; Schieven GL; Vela-Roch N; Fossum D; Dang H; Ogawa N; Talal N
Clinical Immunology Section, Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX.
J Immunol Dec 1 1994, 153 (11) p4880-9

Products of polyamine oxidase activity, at micromolar levels and during a period of 2 to 3 days, down-regulate IL-2 mRNA levels and activity in human lymphocytes. We studied whether this suppression was associated with signal transduction abnormalities. We found that polyamine oxidase activity suppresses both anti-CD3-induced IL-2 production and protein tyrosine phosphorylation. Polyamine oxidase activity also caused a reduction in intracellular calcium mobilization after mitogenic stimulation. The most distal step of CD3-mediated signal transduction is dependent upon transcription factors that regulate a set of genes, including IL-2. We found that polyamine oxidase-treated cells exhibited very low DNA binding activity of two such factors: NFAT and NF-kappa B. On the other hand, AP-1 DNA binding activity was enhanced in polyamine oxidase-treated cells, suggesting a possible role for AP-1 in the human lymphocyte stress response. In accordance with the oxidation dependence of this suppressive mechanism, N-acetylcysteine (NAC; an antioxidant ) significantly reversed the polyamine oxidase effects on lymphokine production and signal transduction. These results suggest that NAC contributes, under oxidizing conditions, to the preservation of immune function . In summary, our data suggest that chronic low-level oxidative stress, via suppression of mitogen-induced transmembrane signaling (protein-tyrosine phosphorylation and calcium mobilization), causes a decrease in the DNA binding activity of transcription factors that regulate the IL-2 gene. This results in decreased IL-2 production.

Stahelin HB
Geriatric University Clinic, Kantonsspital, Basel, Switzerland.
Support Care Cancer (Germany) Nov 1993, 1 (6) p295-7

The potential of a high intake of fresh fruits and vegetables in cancer prevention is well established. Epidemiological studies support carotene, vitamins A, C, E and selenium as the active compounds. Antioxidant properties and direct effects (e.g. inhibition of N-nitrosamine formation or cell-to-cell interactions) are invoked. The role of other trace elements is less clear. The modulation of immune function by vitamins and trace elements remains important and affects survival. In established cancers, the site-specific differences in the diet/cancer relation require appropriate dietary changes, e.g. low fat (20% by energy) in breast cancer, or high vegetable or fruit intake in lung cancer. Single high-dose supplements (e.g. vitamin C) have proved to have no curative or life-prolonging effect. Chemotherapy and radiation increase the requirements for antioxidant compounds. Supplementation can diminish the damage induced by peroxidation. Carefully planned and monitored trials that establish the optimal intake of micronutrients as adjuvants in cancer patients are required. (18 Refs.)

Johnson K; Kligman EW
Dept. of Family and Community Medicine, University of Arizona College of Medicine, Tucson.
Geriatrics Nov 1992, 47 (11) p39-40, 45-9

Disease prevention through dietary management is a cost-effective approach to promoting healthy aging. Fats, cholesterol, soluble fiber, and the trace elements copper and chromium affect the morbidity and mortality of CHD. Decreasing sodium and increasing potassium intake improves control of hypertension. Calcium and magnesium may also have a role in controlling hypertension. The antioxidant vitamins A and beta-carotene, vitamin C, vitamin E, and the trace mineral selenium may protect against types of cancer. A decrease in simple carbohydrates and an increase in soluble dietary fiber may normalize moderately elevated blood glucose levels. Deficiencies of zinc or iron diminish immune function . Adequate levels of calcium and vitamin D can help prevent senile osteoporosis in both older men and women. (27 Refs.)

Jacob RA; Kelley DS; Pianalto FS; Swendseid ME; Henning SM; Zhang JZ; Ames BN; Fraga CG; Peters JH
Western Human Nutrition Research Center, USDA Agricultural Research Service, Presidio of San Francisco, CA 94129.
Am J Clin Nutr Dec 1991, 54 (6 Suppl) p1302S-1309S

To determine nonscorbutic effects of moderate vitamin C deficiency we measured immune function and oxidative damage in eight healthy men (25-43 y) who consumed 5-250 mg/d of ascorbic acid over 92 d on a metabolic unit. During ascorbic acid intakes of 5, 10, or 20 mg/d, subjects attained a state of moderate ascorbic acid deficiency as ascorbic acid concentrations in plasma, leucocytes, semen, and buccal cells dropped to less than 50% of baseline with no scorbutic symptoms observed. No changes in cell proliferation, erythrocyte antioxidant enzymes, and DNA strand breaks were observed; however, blood levels of glutathione and NAD(P) decreased during ascorbic acid deficiency, as did delayed hypersensitivity responsiveness. Concentrations of the oxidatively modified DNA base, 8-hydroxydeoxyguanosine in sperm DNA and fecapentaenes, ubiquitous fecal mutagens, were increased during ascorbic acid depletion. Moderate vitamin C deficiency, in the absence of scurvy, results in alteration of antioxidant chemistries and may permit increased oxidative damage.

Bendich A
Clinical Nutrition, Hoffmann La Roche Inc., Nutley, NJ 07110.
Basic Life Sci 1988, 49 p615-20

Vitamin E, the major lipid-soluble antioxidant present in all cellular membranes, is an important nutrient for optimal immune function . When animals are fed nutritionally complete diets lacking vitamin E, immune responses are adversely affected. Supplementation of these diets with higher than nutritionally adequate levels of vitamin E enhances immune responses. High levels of PUFA are immunosuppressive, and vitamin E can partially overcome this immunosuppression. High levels of vitamin C can protect tissue levels of vitamin E and may indirectly contribute to the immunoenhancement by vitamin E. Severe selenium deficiency is immunosuppressive. Vitamin E can protect some aspects of immune responses from the adverse effects of selenium deficiency. These data clearly indicate that nutrients that affect the overall antioxidant status have important effects on immune functions. In addition, antioxidant nutrient interactions can synergize to overcome the adverse effects of polyunsaturated fatty acids on immune functions (Fig 2). (26 Refs.)

Hornstra G.; Barth C.A.; Galli C.; Mensink R.P.; Mutanen M.; Riemersma R.A.; Roberfroid M.; Salminen K.; Vansant G.; Verschuren P.M.
Dr. G. Hornstra, Department of Human Biology, Maastricht University, PO Box 616, NL-6200 MD, Maastricht Netherlands
British Journal of Nutrition (United Kingdom), 1998, 80/Suppl. 1 (S113-S146)

Cardiovascular disease has a multifactorial aetiology, as is illustrated by the existence of numerous risk indicators, many of which can be influenced by dietary means. It should be recalled, however, that only after a cause-and-effect relationship has been established between the disease and a given risk indicator (called a risk factor in that case), can modifying this factor be expected to affect disease morbidity and mortality. In this paper, effects of diet on cardiovascular risk are reviewed, with special emphasis on modification of the plasma lipoprotein profile and of hypertension. In addition, dietary influences on arterial thrombotic processes, immunological interactions, insulin resistance and hyperhomocysteinaemia are discussed. Dietary lipids are able to affect lipoprotein metabolism in a significant way, thereby modifying the risk of cardiovascular disease. However, more research is required concerning the possible interactions between the various dietary fatty acids, and between fatty acids and dietary cholesterol. In addition, more studies are needed with respect to the possible importance of the postprandial state. Although in the aetiology of hypertension the genetic component is definitely stronger than environmental factors, some benefit in terms of the development and coronary complications of atherosclerosis in hypertensive patients can be expected from fatty acids such as alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. This particularly holds for those subjects where the hypertensive mechanism involves the formation of thromboxane A2 and/or alpha1-adrenergic activities. However, large-scale trials are required to test this contention. Certain aspects of blood platelet function, blood coagulability, and fibrinolytic activity are associated with cardiovascular risk, but causality has been insufficiently proven. Nonetheless, well-designed intervention studies should be initiated to further evaluate such promising dietary components as the various n-3 and n-6 fatty acids and their combination, antioxidants, fibre, etc. for their effect on processes participating in arterial thrombus formation. Long-chain polyenes of the n-3 family and antioxidants can modify the activity of immunocompetent cells, but we are at an early stage of examining the role of immune function on the development of atherosclerotic plaques. Actually, there is little, if any, evidence that dietary modulation of immune system responses of cells participating in atherogenesis exerts beneficial effects. Although it seems feasible to modulate insulin sensitivity and subsequent cardiovascular risk factors by decreasing the total amount of dietary fat and increasing the proportion of polyunsaturated fatty acids, additional studies on the efficacy of specific fatty acids, dietary fibre, and low-energy diets, as well as on the mechanisms involved are required to understand the real function of these dietary components. Finally, dietary supplements containing folate and vitamins B6 and/or B12 should be tested for their potential to reduce cardiovascular risk by lowering the plasma level of homocysteine.

Yaqoob P.
P. Yaqoob, Division of Human Nutrition, School of Biological Sciences, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX United Kingdom
Brazilian Journal of Medical and Biological Research (Brazil), 1998, 31/4 (453-465)

Animal studies suggest that olive oil is capable of modulating functions of cells of the immune system in a manner similar to, albeit weaker than, fish oils. There is some evidence that the effects of olive oil on immune function in animal studies are due to oleic acid rather than to trace elements or antioxidants. Importantly, several studies have demonstrated effects of oleic acid-containing diets on in vivo immune responses. In contrast, consumption of a monounsaturated fatty acid (MUFA)-rich diet by humans does not appear to bring about a general suppression of immune cell functions. The effects of this diet in humans are limited to decreasing aspects of adhesion of peripheral blood mononuclear cells, although there are trends towards decreases in natural killer cell activity and proliferation. The lack of a clear effect of MUFA in humans may be attributable to the higher level of monounsaturated fat used in the animal studies, although it is ultimately of importance to examine the effects of intakes which are in no way extreme. The effects of MUFA on adhesion molecules are potentially important, since these molecules appear to have a role in the pathology of a number of diseases involving the immune system. This area clearly deserves further exploration.

Xiaoguang C.; Hongyan L.; Xiaohong L.; Zhaodi F.; Yan L.; Lihua T.; Rui H.
C. Xiaoguang, Department of Pharmacology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050 China
Journal of Ethnopharmacology (Ireland), 1998, 60/1 (71-78)

Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 similar 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system.

Beisel W.R.
NAIDS, 8210 Ridgelea Court, Frederick, MD 21702-2938 USA
Journal of Nutrition (USA), 1996, 126/10 Suppl. (2611S-2615S)

Malnutrition can have adverse, even devastating effects on the antigen- specific arms of the immune system and on generalized host defensive mechanisms. Protein/energy malnutrition and/or deficiencies of single nutrients that assist in nucleic acid metabolism generally lead to atrophy of lymphoid tissues and dysfunctions of cell-mediated immunity. Deficiencies of single nutrients can impair production of key proteins. Trace element deficiencies are often multifactorial. Essential fatty acid deficiencies can reduce or perturb the synthesis of cytokine-induced eicosanoids. Arginine deficiency can diminish the production of nitric oxide, and deficiencies of antioxidant nutrients can allow increases in the damaging effects of free oxygen radicals. Humoral immunity continues to be maintained, although new primary responses to T-cell-dependent antigens are generally subnormal in both magnitude and quality. Immunological dysfunctions associated with malnutrition have been termed Nutritionally Acquired Immune Deficiency Syndromes (NAIDS). Infants and small children are at great risk because they possess only immature, inexperienced immune systems and very small protein reserves. The combination of NAIDS and common childhood infections is the leading cause of human mortality. NAIDS can generally be corrected by appropriate nutritional rehabilitation, but from a viewpoint highly important to this Workshop, AIDS and NAIDS are intensely synergistic. AIDS-induced malnutrition can lead to the secondary development of NAIDS, with its much broader array of additional immunological dysfunctions. The complex and far reaching insults to the immune system caused by NAIDS, and the synergistic combination of NAIDS and AIDS, thereby hasten the demise of many victims of AIDS. Aggressive nutritional support for children with HIV infections could delay, or lessen, the development of NAIDS and avoidance of NAIDS would improve both quality and length of life.

Liang B.; Watson R.R.
Prevention Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724 USA
Expert Opinion on Investigational Drugs (United Kingdom), 1996, 5/9 (1221-1225)

Nutrition has a profound effect on immunity and health. Nutritional deficiencies impair immune responsiveness, thereby, increase morbidity and mortality. On the other hand, nutritional supplementation often enhances certain aspects of immune function . Vitamin E, as a potent antioxidant and immunostimulant, has recently received a great deal of attention because of its action on immunity and disease aetiology. We recently reviewed the interaction of vitamin E with the immune system, AIDS, circulatory system, and pulmonary system. This paper is a summary of several recent studies on the mechanisms by which vitamin E affects cancer resistance by immunomodulation via nuclear factor-kappaB (NF-kappaB) inhibition.

Traber M.G.; Sies H.
Department of Molecular/Cell Biology, University of California, Berkeley, CA 94720 USA
Annual Review of Nutrition (USA), 1996, 16/- (321-347)

How much vitamin E is enough? An established use of supplemental vitamin E in humans is in the prevention and therapy of deficiency symptoms. The cause of vitamin E deficiency, characterized by peripheral neuropathy and ataxia, is usually malabsorption-a result of fat malabsorption or genetic abnormalities in lipoprotein metabolism. Genetic abnormalities in the hepatic alpha-tocopherol transfer protein also cause vitamin E deficiency- defects in this protein cause an impairment in plasma vitamin E transport. Impaired delivery of vitamin E to tissues, thereby, results in deficiency symptoms. Also discussed is the use of supplemental vitamin E in chronic diseases such as ischemic heart disease, atherosclerosis, diabetes, cataracts, Parkinson's disease, Alzheimer's disease, and impared immune function, as well as in subjects receiving total parenterol nutrition. In healthy individuals, a daily intake of about 15-30 mg of alpha-tocopherol is recommended to obtain 'optimal plasma alpha-tocopherol concentrations' (30 microM or greater).

Liang B.; Lane L.; Watson R.R.
Department of Family Medicine, University of Arizona, Tucson, AZ 85724 USA
Expert Opinion on Investigational Drugs (United Kingdom), 1995, 4/3 (201-211)

As the most powerful and versatile biological defence mechanism of animals and man, the immune system identifies foreign substances and defends the body against their attack. The immune response is concerned not only with providing protection against disease-causing infectious agents, such as bacteria and viruses, that invade the body, but also in recognising and destroying pre-cancerous, tumour-forming cells that develop within the body. Recent evidence indicates that vitamin E is a vital link in optimal immune system functioning and can enhance resistance to disease. The interaction of vitamin E and immune systems, AIDS, oxidative stress, and circulatory and pulmonary system are reviewed in this paper.

Grant J.P.
Duke University Medical Center, Durham, NC 27710 USA
Ann. Surg. (USA), 1994, 220/5 (610-616)

Objective. The author reviews the newer nutritional substrates in use or under investigation for enteral and parenteral nutrition. Management of the critically ill patient remains a significant challenge to clinicians, and it is hoped that dietary manipulations, such as those outlined, may augment host barriers and immune function and improve survival.

Summary Background Data. The role of nutrition in patient well-being has long been recognized, but until the past 25 years, the technology to artificially provide nutrients when patients could not eat was not developed. With current, new methods for enteral and vascular access, patients can be fed nonvolitionally with little difficulty. Continued efforts have been directed toward identifying optimal feeding formulations, which have resulted in a multitude of commercially available products. In the past several years, attention has been turned to evaluation of four specialized nutrients and the use of other substrates as pharmacologic agents.

Methods. Pertinent laboratory and clinical data were reviewed to present the pros and cons for each nutritive substrate.

Conclusions. Medium-chain fatty acids, branched-chain amino acids, and glutamine have been shown to be of clinical benefit and should be in common use in the near future. Short-chain fatty acids still are under investigation. Albumin, vitamins E and C, arginine, glutamine, and omega-3 fatty acids show great promise as pharmacologic agents to manipulate the stress response. Nucleotides remain investigational. Contents Summary. The application of some new nutritional substrates for use in critically ill patients, both as caloric sources and as pharmacologic agents, are reviewed.

Huggins N.D.; Khaled M.A.; Cornwell P.E.; Alvarez J.O.
USA
Res. Common. Subst. Abuse (USA), 1991, 12/4 (209-215)

The plasma levels of some essential nutrients and the lymphocyte CD4 to CD8 ratio were measured in four groups of individuals that included: (a) cocaine and (b) heroin abusers, (c) methadone treated and (d) healthy subjects. Folate and B-carotene levels were lower in the three drug groups while vitamin C was lower in the methadone and heroin subjects. Vitamin E levels were borderline low in the methadone and cocaine groups. The methadone group also showed a significantly higher level of lipid peroxidation which correlated well with the low values observed for the antioxidant nutrients. Interestingly, the methadone group was the only one with a significantly reduced lymphocyte CD4/CD8 ratio.

Isoherranen K; Peltola V; Laurikainen L; Punnonen J; Laihia J; Ahotupa M; Punnonen K
Department of Clinical Chemistry, University of Turku, Finland.
kirsi.isoherranen@utu.fi
J Photochem Photobiol B (Switzerland) Oct 1997, 40 (3) p288-93

We have examined the effects of UVB irradiation, oxidative stress and cytokines on the antioxidant enzymes copper/zinc and manganese superoxide dismutase (CuZnSOD and MnSOD) in HeLa cells. A single dose of UVB irradiation regulated dose-dependently the expression of the 4 kb transcript of MnSOD although it did not have any significant effect on MnSOD enzymatic activity. In contrast, UVB irradiation reduced both the enzymatic activity and the expression of the 0.7 and 0.9 kb mRNA transcripts of CuZnSOD. The cytokines TNF-alpha (1 ng ml-1 and 10 ng ml-1) and IL-6 (100 U ml-1) induced MnSOD activity, and TNF-alpha also upregulated MnSOD mRNA expression. Interestingly, genistein, a soy isoflavone and a tyrosine kinase inhibitor, was able to inhibit the induction of Mn-SOD activity and mRNA expression by TNF-alpha. Enzymatic CuZnSOD activity was depressed by a high dose of H2O2 while IL-6 or TNF-alpha had no effect on CuZnSOD activity. Our results demonstrate that, in addition to enzyme activity level, UVB irradiation can regulate the superoxide dismutases at the mRNA level. We also suggest that UVB irradiation, oxidative stress and cytokines regulate differentially CuZnSOD and MnSOD, and that the activities and expression of these antioxidant enzymes are controlled by distinct mechanisms.

Beck FW; Prasad AS; Kaplan J; Fitzgerald JT; Brewer GJ
Department of Internal Medicine, Wayne State University School of Medicine, Detroit,
Am J Physiol Jun 1997, 272 (6 Pt 1) pE1002-7

We have utilized an experimental model of human zinc deficiency for study of cytokines production by TH1 and TH2 cells. Additionally, we determined ratios of CD4+ to CD8+ and CD4+ CD45RA+ to CD4+CD45RO+ cells and percentages of CD73+ T cytolytic cells in the CD8+ subset. The data were collected during baseline, at the end of the zinc -restricted period, and following zinc repletion. Our results showed that functions of TH1 cells, as evidenced by production of interferon-gamma, interleukin-2 (IL-2), and tumor necrosis factor-alpha, were decreased, whereas functions of TH2 cells (production of IL-4, IL-6, and IL-10) were unaffected by zinc deficiency. Thus an imbalance between TH1 and TH2 cells resulted because of zinc deficiency in humans. Our studies also showed that zinc may be required for regeneration of new CD4+ T lymphocytes and maintenance of T cytolytic cells. We conclude that an imbalance between TH1 and TH2 cells, decreased recruitment of T naive cells, and decreased percentage of T cytolytic cells may account for decreased cell-mediated immune functions in zinc -deficient subjects.

Prasad AS; Beck FW; Grabowski SM; Kaplan J; Mathog RH
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
Proc Assoc Am Physicians Jan 1997, 109 (1) p68-77

Cell-mediated immune dysfunctions and susceptibility to infections have been observed in zinc -deficient human subjects. In this study, we investigated the production of cytokines and characterized the T-cell subpopulations in three groups of mildly zinc -deficient subjects. These included head and neck cancer patients, healthy volunteers who were found to have a dietary deficiency of zinc, and healthy volunteers in whom we induced zinc deficiency experimentally by dietary means. We used cellular zinc criteria for the diagnosis of zinc deficiency. We assayed enzyme-linked immunosorbent assay the production of cytokines from phytohemagglutinin-stimulated peripheral blood mononuclear cells and assessed by flow cytometry the differences in T-cell subpopulations. Our studies showed that the cytokines produced by TH1 cells were particularly sensitive to zinc status, inasmuch as the production of interleukin-2 (IL-2) and interferon-gamma were decreased even though the deficiency of zinc was mild in our subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not affected by zinc deficiency. Natural killer cell lytic activity also was decreased in zinc -deficient subjects. Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+ CD11b-, precursors of cytolytic T cells, were decreased in mildly zinc -deficient subjects. An imbalance between the functions of TH1 and TH2 cells and changes in T-cell subpopulations are most probably responsible for cell-mediated immune dysfunctions in zinc deficiency.

Reinhold D.; Ansorge S.; Grungreiff K.
Dr. K. Grungreiff, Heydeckstr. 9, D-39104 Magdeburg Germany
Journal of Trace Elements in Experimental Medicine (USA), 1997, 10/1 (19-27)

Zinc (zinc ions and/or chelated zinc ) plays an important role in the maintenance of immune function. Patients with chronic liver disease, particularly liver cirrhosis, frequently have endotoxemia, increased serum concentrations of cytokines, e.g., interleukin-6 (IL-6), and reduced serum zinc levels. The aim of the present study was to investigate the effects of zinc (ZnCl2, ZnO, ZnSO4) on DNA synthesis and cytokine production (IL-2, IL-6, IL-10) in pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC). In addition, we examined the effect of long-term zinc supplementation ( zinc -hydrogen-aspartate; UNIZINK 50; 3 x 1 = 29.76 mg/day) on IL-6 and IL-10 serum levels in patients with chronic liver disease (n = 16), all with reduced serum zinc levels. It could be shown that zinc concentrations up to 0.1 mM stimulate DNA synthesis and cytokine production by PWM-stimulated PBMC, whereas higher concentrations (0.2-0.4 mM) have a strongly inhibitory effect. Zinc concentrations exceeding 0.5 mM were found to have a toxic effect on these immune cells. Interestingly, in most patients with chronic liver disease (n = 10), zinc supplementation decreased IL-6, and to a lesser extent, IL-10 serum levels, and normalized the serum zinc concentrations. We conclude that zinc plays a regulatory role in DNA synthesis and cytokine production by PBMC. The critical zinc concentration for immune cells lies in the range of 0.5 mM, which is equivalent to a daily dose of similar45 mg zinc salt. Furthermore, zinc supplementation in chronic liver disease with reduced serum zinc levels appears to normalize IL-6 and IL-10 production.

Fortes C; Forastiere F; Agabiti N; Fano V; Pacifici R; Virgili F; Piras G Guidi L; Bartoloni C; Tricerri A; Zuccaro P; Ebrahim S; Perucci CA
National Institute of Health, Rome, Italy.
J Am Geriatr Soc Jan 1998, 46 (1) p19-26

OBJECTIVE: To determine if either supplemental vitamin A, zinc, or both increases cell - mediated immune response in an older population.

DESIGN: A double-blind, randomized, controlled trial of supplementation with vitamin A and zinc.

SETTING: Casa Di Riposo Roma III, a public home for older people in Rome, Italy.

SUBJECTS: The health and nutritional status of 178 residents were evaluated. One hundred thirty-six residents agreed to participate in the trial and were randomized into four treatment groups, and 118 of these residents completed the trial.

INTERVENTION: The four treatments consisted of: (1) Vitamin A (800 micrograms retinol palmitate); (2) Zinc (25 mg as zinc sulfate); (3) Vitamin A and Zinc (800 micrograms retinol palmitate and 25 mg as zinc sulfate); (4) Placebo capsules containing starch.

MAIN OUTCOME MEASUREMENTS: Immune tests-counts of leucocytes, lymphocytes, T-cell subsets, and lymphocyte proliferative response to mitogens-were measured before and after supplementation.

RESULTS: Zinc increased the number of CD4 + DR + T-cells (P = .016) and cytotoxic T-lymphocytes (P = .005). Subjects treated with vitamin A experienced a reduction in the number of CD3 + T-cells (P = .012) and CD4 + T-cells (P = .012).

CONCLUSIONS: These data indicate that zinc supplementation improved cell - mediated immune response, whereas vitamin A had a deleterious effect in this older population. Further research is needed to clarify the clinical significance of these findings.

Grimble RF
Institute of Human Nutrition, University of Southampton, United Kingdom.
Nutrition Jul-Aug 1998, 14 (7-8) p634-40

The pro-inflammatory cytokines and oxidant molecules produced during the inflammatory response, which follows infection and injury, may be beneficial, or detrimental to the patient, depending on the amounts and contexts in which they are produced. Aberrant or excessive production has been implicated in inflammatory disease, and sepsis. The upregulation of cytokine production by NF kappa B and NFIL-6 activation by oxidants increases the likelihood of cytokine-induced mortality and morbidity. Complex systems exist for the control of cytokine production and oxidant actions. The former include the hormones of the hypothalamo-pituitary-adrenal axis, acute phase proteins, and endogenous inhibitors of interleukin (IL)-1 and tumor necrosis factor (TNF). The latter include endogenously synthesized antioxidants, such as glutathione and dietary antioxidants, such as tocopherols, ascorbates and cachectins. Nutrients change cytokine production and potency by influencing tissue concentrations of many of the molecules involved in cytokine biology. Monounsaturated fatty acids and omega-3 polyunsaturated fatty acids (PUFAs) suppress TNF and IL-1 production and actions, while n-6 PUFAs exert the opposite effect. Changes in eicosanoid production are more likely to underlie this effect than alterations in membrane fluidity. Low antioxidant intake results in enhanced cytokine production and effects. The anorexia that follows infection and injury, may be purposeful to permit release of substrate from endogenous sources to support and control the inflammatory process. Therefore, prior as well as concurrent nutrient intake are of importance in determining the outcome of the inflammatory response. (88 Refs.)

Santos MS; Gaziano JM; Leka LS; Beharka AA; Hennekens CH; Meydani SN
Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Am J Clin Nutr Jul 1998, 68 (1) p164-70

We showed previously that natural killer (NK) cell activity is significantly greater in elderly men supplemented with beta -carotene than in those taking placebo. In an attempt to determine the mechanism of beta -carotene 's effect, we analyzed the production of NK cell-enhancing cytokines (interferon alpha, interferon gamma, and interleukin 12). Boston-area participants in the Physicians' Health Study (men aged 65-88 y; mean age, 73 y) who had been supplemented with beta -carotene (50 mg on alternate days) for an average of 12 y were enrolled in a randomized, placebo-controlled, double-blind study. Elderly subjects taking beta -carotene supplements had significantly greater plasma beta -carotene concentrations than those taking placebo. Beta -carotene -supplemented elderly men had significantly greater NK cell activity than did elderly men receiving placebo. Percentages of NK cells (CD16+CD56+) were not significantly different between the beta -carotene and placebo groups. Production of interleukin 12, interferon alpha, or concanavalin A-stimulated interferon gamma by cultured peripheral blood mononuclear cells was not significantly different between beta-carotene-supplemented elderly and those taking placebo. Our results indicate that beta -carotene -induced enhancement of NK cell activity is not mediated by changes in percentages of CD16+CD56+ NK cells nor through up-regulation of interleukin 12 or interferon alpha.

Spapen H; Zhang H; Demanet C; Vleminckx W; Vincent JL; Huyghens L
Department of Intensive Care, Academic Hospital, Vrije Universiteit, Brussels, Belgium.
Chest Jun 1998, 113 (6) p1616-24

STUDY OBJECTIVE: To assess the effects of adjunctive treatment with N-acetyl-L-cysteine (NAC) on hemodynamics, oxygen transport variables, and plasma levels of cytokines in patients with septic shock.

DESIGN: Prospective, randomized, double-blind, placebo-controlled study.

SETTING: A 24-bed medicosurgical ICU in a university hospital.

PATIENTS: Twenty-two patients included within 4 h of diagnosis of septic shock.

INTERVENTIONS: Patients were randomly allocated to receive either NAC (150 mg/kg bolus, followed by a continuous infusion of 50 mg/kg over 4 h; n= 12) or placebo (n=10) in addition to standard therapy.

MEASUREMENTS: Plasma concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor-alpha receptor-p55 (sTNFR-p55) were measured by sensitive immunoassays at 0, 2, 4, 6 and 24 h. Pulmonary artery catheter-derived hemodynamics, blood gases, hemoglobin, and arterial lactate were measured at baseline, after infusion (4 h), and at 24 h.

RESULTS: NAC improved oxygenation (PaO2/FIO2 ratio, 214+/-97 vs 123+/-86; p<0.05) and static lung compliance (44+/-11 vs 31+/-6 L/cm H2O; p<0.05) at 24 h. NAC had no significant effects on plasma TNF, IL-6, or IL-10 levels, but acutely decreased IL-8 and sTNFR-p55 levels. The administration of NAC had no significant effect on systemic and pulmonary hemodynamics, oxygen delivery, and oxygen consumption. Mortality was similar in both groups (control, 40%; NAC, 42%) but survivors who received NAC had shorter ventilator requirement (7+/-2 days vs 20+/-7 days; p<0.05) and were discharged earlier from the ICU (13+/-2 days vs 32+/-9 days; p<0.05).

CONCLUSION: In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.

Blok WL; Deslypere JP; Demacker PN; van der Ven-Jongekrijg J; Hectors MP; van der Meer JW; Katan MB
Department of General Internal Medicine, University Hospital Nijmegen, The Netherlands.
Eur J Clin Invest (England) Dec 1997, 27 (12) p1003-8

Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.

Faruqi RM; Poptic EJ; Faruqi TR; De La Motte C; DiCorleto PE
Department of Cell Biology, Cleveland Clinic Foundation, Ohio 44195, USA.
Am J Physiol Aug 1997, 273 (2 Pt 2) pH817-26

We have examined the effects of N-acetyl-L- cysteine (NAC), a well-characterized, thiol-containing antioxidant, on agonist-induced monocytic cell adhesion to endothelial cells (EC). NAC inhibited interleukin-1 (IL-1 beta)-induced, but not basal, adhesion with 50% inhibition at approximately 20 mM. Monocytic cell adhesion to EC in response to tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), alpha-thrombin, or phorbol 12-myristate 13-acetate (PMA) was similarly inhibited by NAC. Unlike published studies with pyrrolidinedithiocarbamate, which specifically inhibited vascular cell adhesion molecule 1 (VCAM-1), NAC inhibited IL-1 beta-induced mRNA and cell surface expression of both E-selectin and VCAM-1. NAC had no effect on the half-life of E-selectin or VCAM-1 mRNA. Although NAC reduced nuclear factor-kappa B (NF-kappa B) activation in EC as measured by gel-shift assays using an oligonucleotide probe corresponding to the consensus NF-kappa B binding sites of the VCAM-1 gene (VCAM-NF-kappa B), the antioxidant had no appreciable effect when an oligomer corresponding to the consensus NF-kappa B binding site of the E-selectin gene (E-selectin-NF-kappa B) was used. Because NF-kappa B has been reported to be redox sensitive, we studied the effects of NAC on the EC redox environment. NAC caused an expected dramatic increase in the reduced glutathione (GSH) levels in EC. In vitro studies demonstrated that whereas the binding affinity of NF-kappa B to the VCAM-NF-kappa B oligomer peaked at a GSH-to-oxidized glutathione (GSSG) ratio of approximately 200 and decreased at higher ratios, the binding to the E-selectin-NF-kappa B oligomer appeared relatively unaffected even at ratios > 400, i.e., those achieved in EC treated with 40 mM NAC. These results suggest that NF-kappa B binding to its consensus sequences in the VCAM-1 and E-selectin gene exhibits marked differences in redox sensitivity, allowing for differential gene expression regulated by the same transcription factor. Our data also demonstrate that NAC increases the GSH-to-GSSG ratio within the EC suggesting one possible mechanism through which this antioxidant inhibits agonist-induced monocyte adhesion to EC.

Mol MJ; de Rijke YB; Demacker PN; Stalenhoef AF
Department of Medicine, University Hospital Nijmegen, Netherlands.
Atherosclerosis (Ireland) Mar 21 1997, 129 (2) p169-76

To evaluate the role of both oxidation and inflammation in atherosclerosis, we compared LDL oxidizability, in vivo lipid and cholesterol oxidation, and basal and lipopolysaccharide (LPS)-stimulated production of various cytokines in normolipidemic patients with diabetes mellitus (DM: n = 11), cigarettes smokers (n = 14). In addition, the effects of vitamin E (600 I.U./day for 4 weeks) on these parameters were evaluated. Initial LDL oxidation characteristics before and after vitamin E were identical in the 3 groups. Plasma thiobarbituric acid reactive substances were higher in DM and smokers versus controls (0.77 +/- 0.22, 0.74 +/- 0.14 versus 0.62 +/- 0.10 mumol malondialdehyde equivalents/l, respectively; P versus controls < 0.05) and normalized after vitamin E supplementation. Total plasma oxysterols were higher in smokers versus controls (354 +/- 104 versus 265 +/- 66 nmol/l, P < 0.05) and unaffected by vitamin E. The basal and LPS-stimulated levels of interleukin-1 beta and tumour necrosis factor alpha (TNF alpha) and the basal level of interleukin-1-receptor antagonist (IL-1RA) were identical for the 3 groups. LPS-stimulated IL-1RA was higher in DM versus controls (10.7 +/- 2.0 versus 8.1 +/- 1.7 pmol/l, P < 0.05). After vitamin E, TNF alpha dropped in controls and smokers, and IL-1RA in smokers only. Results suggest increased in vivo oxidative stress and inflammation in DM and smoking, which is partly overcome by vitamin E.

Chuntrasakul C, Siltharm S, Sarasombath S, Sittapairochana C, Leowattana W, Chockvivatanavanit S, Bunnak A
Research Center for Nutritional Support, Siriraj Hospital.
J Med Assoc Thai 1998 May;81(5):334-43

To evaluate the nutritional, metabolic and immune effects of dietary arginine, glutamine and omega-3 fatty acids (fish oil) supplementation in immunocompromised patients, we performed a prospective study on the effect of immune formula administered to 11 severe trauma patients (average ISS = 24), 10 burn patients (average % TBSA = 48) and 5 cancer patients. Daily calorie and protein administration were based on the patient's severity (Stress factor with the range of 35-50 kcal/kg/day and 1.5-2.5 g/kg/day, respectively) Starting with half concentration liquid immune formula through nasogastric tube by continuous drip at 30 ml/h and increasing to maximum level within 4 days. The additional energy and protein requirement will be given either by parenteral or oral nutritional support. Various nutritional, metabolic, immunologic and clinical parameters were observed on day 0 (baseline), day 3, 7, and 14. Analysis was performed by paired student-t test. Initial mean serum albumin and transferrin showed mild (trauma) to moderate (burn and cancer) degree of malnutrition. Significant improvement of nutritional parameters was seen at day 7 and 14 in trauma and burn patients. Significant increase of total lymphocyte count (day 7, P < 0.01), CD4 + count (day 7, p < 0.01), CD8 + count (day 7, p <0.0005 & day 14, p < 0.05), complement C3 (day 7, p < 0.005 day 14, p < 0.01), IgG (day 7, and 14, p < 0.0005), IgA (day 7, p < 0.0005 & day 14, p < 0.05), in all patients. C-reactive protein decreased significantly on day 7 (p < 0.0005) and day 14 (p < 0.005). 3 cases of burn wound infection, one case of UTI and one case of sepsis were observed. Two cases of hyperglycemia in burn, 3 cases of hyperbilirubinemia in trauma, 10 cases of elevated LFT (5 trauma/5 burn), and one case of hyponatremia in cancer patients were observed. Two cases of nausea, 4 cases of vomiting, 5 cases of diarrhea (< 3 times/day), 2 cases of abdominal cramp, 1 case of distension were observed. The feeding of IMMUNE FORMULA was well tolerated and significant improvement was observed in nutritional and immunologic parameters as in other immunoenhancing diets. Further clinical trials of prospective double-blind randomized design are necessary to address the so that the necessity of using immunonutrition in critically ill patients will be clarified.

Sayed-Ahmed MM; Shaarawy S; Shouman SA; Osman AM
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
Pharmacol Res, 39(4). 289-5 1999 Apr

Biopharmacological evaluations of the protective effects of L-carnitine (a naturally occurring quaternary ammonium compound) against doxorubicin-induced metabolic damage were carried out in isolated cardiac myocytes and in isolated rat heart mitochondria. Perfusion of the heart with DOX (0.5 mM) caused a significant 70% inhibition of palmitate oxidation in cardiac myocytes, while L-carnitine (5 mM) perfusion caused stimulation which accounted for 37%. Perfusion of the heart with L-carnitine after 10-min perfusion with DOX (0.5 mM) caused 88% reversal of DOX-induced inhibition of palmitate oxidation in cardiac cells. In rat heart mitochondria, DOX has no effect on either palmitate oxidation or acyl-CoA synthetase activity, whereas Enoximone (c-AMP-dependent phosphodiesterase inhibitor), caused a significant inhibition of palmitate oxidation and acyl-CoA activity (40 and 27%, respectively). The oxidation of palmitoyl-CoA, an index of carnitine palmitoyltransferse reaction was significantly inhibited by DOX as a function of DOX concentration. Preincubation of mitochondria with L-carnitine caused reversal of DOX-induced inhibition of palmitoyl-CoA oxidation depending on the concentration of L-carnitine. Moreover, L-carnitine treatment did not interfere with the cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. The findings of this study may suggest that inhibition of fatty acid oxidation in the heart is at least a part of doxorubicin cardiotoxicity and that L-carnitine can be used to prevent the doxorubcin-induced cardiac metabolic damage without interfering with its antitumour activities. Copyright 1999 The Italian Pharmacological Society.

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Linking vitamin A and childhood immunizations

Semba R.D.
Wilmer Building, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287 USA
Journal of Nutritional Immunology (USA), 1996, 4/1-2 (87-109)

Although studies conducted over the last twenty-five years have demonstrated that vitamin A and related retinoids are immune enhancers, the use of vitamin A and related retinoids to enhance responses to immunization has been limited. Numerous animal studies have now demonstrated that vitamin A and related retinoids, when given at or prior to immunization, will enhance antibody responses and cell-mediated immune responses to protein antigens. Recent studies with humans show that vitamin A supplementation enhances the IgG response to tetanus toxoid, and that related retinoids can be used to enhance antibody responses to protein antigens. Vitamin A enhances immune responses to poor immunogens, and this may be relevant to vaccines which are characterized by low seroconversion rates. Although most known adjuvants have too many side effects for human use, vitamin A and related retinoids appear to enhance antibody and cell-mediated immunity without severe side effects. Vitamin A, through its metabolites, acts to modify biological responses through specific nuclear receptors which activate gene transcription. Thus, the mechanism for immune enhancement by vitamin A appears to be different from that of known adjuvants. Vitamin A and related retinoids have potential as a safe and effective means of enhancing immune responses to vaccination antigens.

Interleukin-2 and human immunodeficiency virus infection: Pathogenic mechanisms and potential for immunologic enhancement

Kinter A.; Fauci A.S.
LIR, NIAID, NIH, Building 10, 10 Center Drive, MSG-1576, Bethesda, MD 20892-1576 USA
Immunologic Research (Switzerland), 1996, 15/1 (1-15)

A hallmark of human immunodeficiency virus (HIV) infection is the progressive loss of CD4+ T lymphocytes; however, qualitative defects in immune responses occur prior to the precipitous drop CD4+ T cell numbers. One of the first immunologic defects to be described in HIV-infected individuals is a deficiency in interleukin (IL)-2 production. The addition of IL-2 in vitro to cultures of mononuclear cells from HIV-infected individuals partially or completely restored certain defective cellular immune responses. However, production of or addition of IL-2 has also been associated with increased viral replication in infected T cells. These observations underscore the pernicious correlation between immune activation and HIV replication. However, recent in vitro and in vivo studies have provided promising preliminary results suggesting that, at least at certain stages of disease, the benefits of IL-2-mediated immune enhancement may outweigh or override the inductive effects of this cytokine on HIV production.

Regulation of the immune response by dehydroepiandrosterone and its metabolites

Loria R.M.; Padgett D.A.; Huynh P.N.
Department of Microbiology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298-09678 USA
Journal of Endocrinology (United Kingdom), 1996, 150/Suppl. (S209-S220)

Dehydroepiandrosterone (5-androsten-3beta-ol-17-one, DHEA) has been shown to protect mice from a variety of lethal infections. This includes, but is not limited to, infection with viruses (herpes virus type 2, coxsackie virus B4 (CB4)), bacteria (Enterococcus faecalis, Pseudomonas aeruginosa), and a parasite (Cryptosporidium parvum). We have previously reported that androstenediol (5-androstene-3beta,17beta-diol, AED), derived from DHEA, is at least 100 x more effective in up-regulating systemic resistance against CB4 infection than its precursor. Furthermore, androstenetriol (5-androstene-3beta,7beta,17beta-triol, AET) which is formed by 7beta hydroxylation of AED, was more effective against CB4 infection than its precursor, AED. Neither steroid, however, has shown any significant direct antiviral effects. The in vitro influences of DHEA, AED and AET on a mitogen-induced mixed splenocyte proliferation assay were determined. The results showed that DHEA suppressed the proliferation of concanavalin A (ConA)- or lipopoly-saccharide-activated cultures in a dose-dependent manner. AED had little influence on the activation response. However, AET potentiated the response to both mitogens significantly above the control level. The regulation of interleukin (IL)-2 and IL-3 secretion from ConA-activated lymphocytes was analogous to these observations. These functions were depressed by DHEA, unaffected by AED, and potently increased by AET. Moreover, the classic immunosuppressive effects of hydrocortisone on ConA-induced lymphocyte proliferation, as well as IL-2 and IL-3 production, were unaffected by co-culture with DHEA and only minimally counteracted by AED. In contrast, AET significantly counteracted the effect of hydrocortisone when co-cultured together. These data show that while DHEA, AED and AET each function in a similar manner in vivo, in vitro their effects are dramatically different from one another with only AET potentiating the cellular response by increasing lymphocyte activation and counteracting the immunosuppressive activity of hydrocortisone.

Cellular activation induced by BCG is a PTK-dependent event

Mendez-Samperio P.; Hernandez-Garay M.; Vazquez A.N.
Departamento de Inmunologia, ENCB, IPN, Carpio y Plan de Ayala, Mexico, D.F. 11340 Mexico
Cellular Immunology (USA), 1996, 171/1 (147-152)

Mycobacterial antigens including BCG stimulate human peripheral blood mononuclear cells resulting in cellular proliferation and the release of inflammatory cytokines such as TNF-alpha. However, the signal transduction mechanisms responsible for the BCG-induced cell activation are not completely understood. In this study, we investigated the role of PTK as a signal transduction pathway in BCG-induced cell activation, with the use of twoPTK inhibitors (genistein and tyrphostin). Our results indicated that genistein significantly inhibited BCG-induced cell growth determined by thymidine uptake in a dose-dependent manner. BCG-induced TNF-alpha secretion was completely suppressed by genistein in a dose-dependent manner, producing 92% inhibition at a concentration of 50 microM. In addition, strong inhibition (81%) of BCG-induced TNF-alpha secretion was observed with tyrphostin (30 microM), another specific protein tyrosine kinase with a different mechanism of action. These inhibitory effects were not attributed to an alteration in cell viability as judged by trypan blue staining, and were not due to LPS contamination. On the other hand, monoclonal antibodies directed against HLA-DR and DQ inhibited the BCG-induced secretion of TNF-alpha. Taken together, these findings suggest that PTK may play an essential role in BCG-induced cellular activation.

Stress-induced suppression of the cellular immune reactions: On the neuroendocrine control of the immune system

Hassig A.; Wen-Xi L.; Stampfli K.
Studiengruppe Ernahrung/Immunitat, Elisabethenstrasse 51, CH-3014 Bern Switzerland
Medical Hypotheses (United Kingdom), 1996, 46/6 (551-555)

Immune competence is considered as a state of equilibrium between humoral and cellular immunity. This notion fits well with the functionally antagonistic cytokine profiles in cell groups of CD4+-helper cells as described by Mosmann and Coffman. The Th-1 cells release mainly IL-2, IL-12 and IFNgamma and thereby stimulate the cellular immune reactions. Conversely, the Th-2 cells produce predominantly IL-4, IL-6 and IL-10, thus enhancing humoral immune reactions. Recently, it has been shown that the lymphokine profiles in Th-2 are linked to changes of the humoral balance between cortisol and dehydroepiandrosterone. These studies show that there exist states of equilibrium between T- and B-cell-mediated immune reactions, which may selectively be altered to the disadvantage of the T-cellular immunity by a stress-induced enhancement of cortisol release. In an attempt to restitute stress-induced immunosuppression, a dampening of the cortisol release hormone in the hypothalamus should, therefore, be of primary importance.

Localization and synthesis of acetylcholine in human leukemic T cell lines

Fujii T.; Tsuchiya T.; Yamada S.; Fujimoto K.; Suzuki T.; Kasahara T.; Kawashima K.
Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105 Japan
Journal of Neuroscience Research (USA), 1996, 44/1 (66-72)

In order to clarify the origin of acetylcholine (ACh) in human blood, we measured the content and synthesis activity of ACh in several human leukemic cell lines. The intracellular ACh content determined by a specific and sensitive radioimmunoassay in the human leukemic T cell lines, HSB-2, MOLT- 3, and CEM, was 79.6, 36.2, and 9.5 pmol/106 cells, respectively. These values were 9-70-fold higher than those of other cell lines, including a helper T cell line, Jurkat. Stimulation of HSB-2 and MOLT-3 by phytohemagglutinin (PHA) increased both the intracellular content and release of ACh into the culture medium, but did not influence the intracellular content and release of ACh in CEM. ACh synthesis activity was found in all the T cell lines tested. Bromoacetylcholine (100 microM), a choline acetyltransferase (CHAT) inhibitor, and bromoacetyl-L-carnitine (100 microM), a carnitine acetyltransferase (CarAT) inhibitor, decreased ACh-synthesizing activity in MOLT-3, and HSB-2 and CEM, by about 50% and 30%, respectively, indicating that both CHAT, and to a lesser extent CarAT, are involved in ACh synthesis in T cells. These results suggest that T lymphocytes have the potential to synthesize and release ACh, which may play a role in regulating T cell-dependent immune responses.

Adrenal and gonadal steroid hormone deficiency in the etiopathogenesis of rheumatoid arthritis

Wilder R.L.
NIAMS, NIH, National Institutes of Health, Bethesda, MD 20892 USA
Journal of Rheumatology (Canada), 1996, 23/Suppl. 44 (10-12)

Rheumatoid arthritis (RA) is a multifactonal disease in which both environmental and genetic factors play a role. Data also suggest that neuroendocrine factors are involved. I briefly summarize observations that support this hypothesis. RA is characterized by striking age-sex disparities. The incidence of disease in women increases steadily from the age of menarche to its maximal incidence around menopause. The disease is uncommon in men under age 45, but its incidence increases rapidly in older men and approaches the incidence in women. These observations strongly suggest that androgens play a major suppressive role, and, in fact, testosterone levels are depressed in most men with RA. Mechanistically, many data indicate that testosterone suppresses both cellular and humoral immune responses. Dehydroepiandrosterone (DHEA), an adrenal product, is the major androgen in women. Its production is strikingly dependent upon age. Peak production is in the 2nd and 3rd decades, but levels decline precipitously thereafter. DHEA levels are low in both men and women with RA, and recent data show that levels of this hormone may be depressed before the onset of disease. The role of DHEA in immune diseases, however, is controversial. The menopausal peak of RA onset suggests estrogen and/or progesterone deficiency play-a role in the disease, and many data Indicate that estrogens suppress cellular immunity but stimulate humoral immunity, i.e., deficiency promotes cellular (Th1-type) immunity. Recent data also indicate that progesterone stimulates a switch for Th1 to Th2-type immune responses, RA often develops or flares in the postpartum period, particularly if the mother breastfeeds. This is again consistent with gonadal steroid deficiency playing a role in the onset of disease. Breastfeeding is associated with blunted hypothalamic-pitu itary-adrenal function and elevated prolactin synthesis. Gonadal and adrenal steroid hormone deficiency, plus elevated prolactin, probably greatly facilitates the expression of Th1-type immunity, which is widely believed to be critical in the pathogenesis of RA. By contrast, RA typically remits during pregnancy, in parallel with the increasing levels of corticosteroids, estrogens, and progesterone. Pregnancy is characterized by a shift in immune function from Th1-type to Th2-type. Oral contraceptives, which generate a condition of pseudopregnancy, also decrease the risk of RA. These data argue that adrenal and gonadal steroid hormones suppress the development. of RA. Several studies indicate that corticosteroid production is inappropriately low in patients with RA, and are reminiscent of observations in Lewis rat models of chronic erosive arthritis. In summary, a growing body of data indicate that RA develops as a consequence of a deficiency in both adrenal and gonadal steroid hormone production. This hypothesis clearly has potential clinical implications.

Can the length of hospital stay be influenced by enteral immunonutrition?

Bastian L.; Weimann A.; Weissflog D.; Frei A.; Regel G.
Dr. L. Bastian, Unfallchirurgische Klinik, Medizinische Hochschule, D-30623 Hannover Germany
Anasthesiologie und Intensivmedizin (Germany), 1997, 38/3 (137-147)

The balance of current clinical data suggests that early enteral nutrition may influence infectious complications in the critically ill patients. Certain nutrients may affect organ function, independent of their general nutritional effects. Four of these nutrients are arginine, nucleotides, omega-3-fatty acids and glutamine. The target cells for the action of these nutrients appear to be T-lymphocytes and macrophages. An enteral nutrition enriched with such nutrients is called 'immunonutrition'. Recent evidence has suggested that an immunonutrition can have a beneficial effect on the prevention of infectious complications and SIRS, reduction of ventilator days, ICU- and hospital stay. This seems to be translated into a reduction in hospital charges. Beside a therapeutic approach with specific inhibitors and receptor antagonists the so called 'immunonutrition' seems to have a place in the therapy of the critically ill patient.

Immunohistochemical localization of cysteine-rich intestinal protein in rat small intestine

Fernandes P.R.; Samuelson D.A.; Clark W.R.; Cousins R.J.
R.J. Cousins, Food Science/Human Nutrition Dept., Center for Nutritional Sciences, Univ. of Florida, PO Box 110370, Gainesville, FL 32611 USA
American Journal of Physiology - Gastrointestinal and Liver Physiology ( USA), 1997, 272/4 35-4 (G751-G759)

Cysteine-rich intestinal protein (CRIP) is a LIM (cysteine-rich motif of leu-11, isl-1, and mec-3 genes) domain protein with a double zinc finger motif. The protein is abundantly expressed in the intestine, peritoneal macrophages, and peripheral blood mononuclear cells. The function of CRIP is not known. The purpose of this study was to determine the cellular distribution of CRIP in rat intestine, as an initial step toward eventual determination of a function. Immunohistochemical and immunogold labeling electron microscopy using a purified polyclonal rabbit antibody to a synthetic peptide representing a zinc finger domain of rat CRIP were carried out on sections of rat duodenum. Western blotting was used to detect signal specificity of the antibodies. These immunohistochemical and electron microscopy studies showed particularly high abundance of CRIP in the cytoplasmic granules of Paneth cells of the intestine. Some evidence of CRIP expression was also found in cells of the villus tip, but abundance was less than that found in the Paneth cells. The localization of CRIP in Paneth cells and its presence in mononuclear cells suggests that CRIP may be involved in host defense mechanisms and/or tissue differentiation/remodeling processes common to these cell types.

Effect of early vitamin A supplementation on cell-mediated immunity in infants younger than 6 mo

Rahman M.M.; Mahalanabis D.; Alvarez J.O.; Wahed M.A.; Islam M.A.; Habte D.
J.O. Alvarez, Department of International Health, University of Alabama at Birmingham, 106 Tidwell Hall, Birmingham, AL 35294-0008 USA
American Journal of Clinical Nutrition (USA), 1997, 65/1 (144-148)

One hundred twenty infants were randomly as signed to receive either 15 mg vitamin A or placebo with each of three DPT/OPV (diphtheria, pertussis, tetanus/oral polio vaccine) immunizations at monthly intervals. Sixty-two received vitamin A and 58 received placebo. One month after the third supplementation dose, the response to the delayed cutaneous hypersensitivity test (multitest cell-mediated immunity (CMI) skin evaluation) for tetanus, diphtheria, and tuberculin (purified protein derivative, PPD) was the same in the vitamin A and placebo infants. The number of anergic infants was 17 (27%) and 19 (33%) in the vitamin A and placebo groups, respectively. The number of positive tests among well-nourished infants was significantly higher than that in malnourished infants irrespective of supplementation (P < 0.001). Among the infants with adequate serum retinol concentrations (> 0.7 micromol/L) after supplementation, the vitamin A-supplemented infants had a significantly higher proportion of positive CMI tests than the placebo infants (chi-square test: 8.99, P = 0.008). Among the infants with low serum retinol concentrations (< 0.7 micromol/L) after supplementation, vitamin A supplementation had no effect on CMI response. These results indicate that CMI in young infants was positively affected by vitamin A supplementation only in those infants whose vitamin A status was adequate (ie, serum retinol > 0.7 micromol/L) at the time of the CMI test. CMI was consistently better in well-nourished infants irrespective of supplementation.

Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation

Santos M.S.; Meydani S.N.; Leka L.; Wu D.; Fotouhi N.; Meydani M.; Hennekens C.H.; Gaziano J.M.
Nutritional Immunology Laboratory, Jean Mayer USDA HNRCA, Tufts University, 711 Washington Street, Boston, MA 02111 USA
American Journal of Clinical Nutrition (USA), 1996, 64/5 (772-777)

Natural killer (NK) cell activity has been postulated to be an immunologic link between beta-carotene and cancer prevention. In a cross- sectional, placebo-controlled, double-blind study we examined the effect of 10-12 y of beta-carotene supplementation (50 mg on alternate days) on NK cell activity in 59 (38 middle-aged men, 51-64 y; 21 elderly men, 65-86 y) Boston area participants in the Physicians' Health Study. No significant difference was seen in NK cell activity due to beta-carotene supplementation in the middle-aged group. The elderly men had significantly lower NK cell activity than the middle-aged men; however, there was no age-associated difference in NK cell activity in men supplemented with beta-carotene. beta-carotene- supplemented elderly men had significantly greater NK cell activity than elderly men receiving placebo. The reason for this is unknown; however, it was not due to an increase in the percentage of NK cells, nor to an increase in interleukin 2 (IL-2) receptor expression, nor to IL-2 production. beta- carotene may be acting directly on one or more of the lytic stages of NK cell cytotoxicity, or on NK cell activity-enhancing cytokines other than IL-2, such as IL-12. Our results show that long-term beta-carotene supplementation enhances NK cell activity in elderly men, which may be beneficial for viral and tumoral surveillance.

Molecular mechanisms of vitamin A action and their relationship to immunity

Chytil F.
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232-0146 USA
Journal of Nutritional Immunology (USA), 1996, 4/1-2 (35-45)

This paper addresses the molecular mechanisms by which vitamin A (retinol) could influence the immune system, and the relationships of these mechanisms to the better known mechanisms in which retinol affects other non-immune biological phenomena, such as epithelial cell differentiation, embryogenesis, and organ development. In many tissues, the sequential molecular actions of the retinoids have been well defined. However, major questions remain about the action of retinoids on lymphocytes. Much evidence indicates an important role for vitamin A molecules (called retinoids) in the function of both the cellular and the humoral arms of the immune system. Attention should also be paid to the nuclear retinoic acid receptors (RAR) in various cells. These protein receptors are similar to those which bind steroids, thyroid hormones, and vitamin D. The nuclear retinoic acid receptors, and another analogous receptor family initially called 'orphan receptor' now designated 'nuclear RXR receptors,' together with other described cellular binding proteins, appear to be involved in regulating, as well as transmitting, the effects of the retinoids on the molecular machinery of various body cells, including the lymphocytes.

Historical overview of nutrition and immunity, with emphasis on vitamin A

Beisel W.R.
Dept Molecular Microbiol Immunology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD USA
Journal of Nutritional Immunology (USA), 1996, 4/1-2 (1-16)

In retrospect, the foundations for Nutritional Immunology emerged in the early 1800s with the finding that severe malnutrition would lead to thymic atrophy, and for most of that century, all evidence for a relationship between malnutrition and the immune system was based on anatomical findings. With the discovery of vitamins, it became evident that single essential nutrients each played an important role in host resistance. During the 1920s and 1930s, vitamin A became known as the 'anti-infective' vitamin, and the first attempts were made to use vitamin A therapeutically during infectious illnesses. With the gradual emergence of knowledge about the details of immune system functions, malnutrition was found to depress humoral immunity (by reducing the production of antibodies to vaccines), cell mediated;immunity (by inducing anergy to skin tests), and allergic symptoms. But the first systematic studies of immunonutritional interrelationships in laboratory animals were initiated in 1947 by Abraham E. Axelrod and his students. Human studies followed soon thereafter, and by the late 1970s the field of nutritional immunology was well established. The importance of vitamin A in reducing the morbidity and mortality caused by measles and other infectious illnesses has now re-emerged. The potential importance of correcting vitamin A deficiency, as a practical and inexpensive public health strategy to reduce childhood mortality in the Third World, is being tested in many locations, with The Johns Hopkins School of Hygiene and Public Health playing an important role.

Vitamin E supplementation and in vivo immune response in healthy elderly subjects: A randomized controlled trial

Meydani S.N.; Meydani M.; Blumberg J.B.; Leka L.S.; Siber G.; Loszewski R.; Thompson C.; Pedrosa M.C.; Diamond R.D.; Stollar B.D.
Dr. S.N. Meydani, Nutritional Immunology Laboratory, JM USDA HNRCA, Tufts University, 711 Washington St, Boston, MA 02111 USA
Journal of the American Medical Association (USA), 1997, 277/17 (1380-1386)

Objective. - To determine whether long-term supplementation with vitamin E enhances in vivo, clinically relevant measures of cell-mediated immunity in healthy elderly subjects.

Design. - Randomized, double-blind, placebo- controlled intervention study.

Setting and Participants. - A total of 88 free-living, healthy subjects at least 65 years of age. Intervention. - Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days.

Main Outcome Measures. - Delayed- type hypersensitivity skin response (DTH); antibody response to hepatitis B, tetanus and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin were assessed before and after supplementation.

Results. - Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3- fold, respectively), 60-mg/d (41% and 3-told, respectively), and 800-mg/d (49% and 2.5-fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (>48.4 micromol/L (2.08 mg/dL)) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed.

Conclusions. - Our results indicate that a level of vitamin E greater than currently recommended enhances certain clinically relevant in vivo indexes of T-cell-mediated function in healthy elderly persons. No adverse effects were observed with vitamin E supplementation.

Zinc deficiency: Changes in cytokine production and T-cell subpopulations in patients with head and neck cancer and in noncancer subjects

Prasad A.S.; Beck F.W.J.; Grabowski S.M.; Kaplan J.; Mathog R.H.
USA
Proceedings of the Association of American Physicians (USA), 1997, 109/1 (68-77) 50X

Cell-mediated immune dysfunctions and susceptibility to infections have been observed in zinc-deficient human subjects. In this study, we investigated the production of cytokines and characterized the T-cell subpopulations in three groups of mildly zinc-deficient subjects. These included head and neck cancer patients, healthy volunteers who were found to have a dietary deficiency of zinc, and healthy volunteers in whom we induced zinc deficiency experimentally by dietary means. We used cellular zinc criteria for the diagnosis of zinc deficiency. We assayed enzyme-linked immunosorbent assay the production of cytokines from phytohemagglutinin- stimulated peripheral blood mononuclear cells and assessed by flow cytometry the differences in T-cell subpopulations. Our studies showed that the cytokines produced by TH1 cells were particularly sensitive to zinc status, inasmuch as the production of interleukin-2 (IL-2) and interferon-gamma were decreased even though the deficiency of zinc was mild in our subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not affected by zinc deficiency. Natural killer cell lytic activity also was decreased in zinc-deficient subjects. Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+ CD11b-, precursors of cytolytic T cells, were decreased in mildly zinc-deficient subjects. An imbalance between the functions of TH1 and TH2 cells and changes in T-cell subpopulations are most probably responsible for cell-mediated immune dysfunctions in zinc deficiency.

Immunotherapy of leprosy

Katoch K.
India
Indian Journal of Leprosy (India), 1996, 68/4 (349-361)

Immunotherapy aims to modify the defective cell-mediated immune response in a section of leprosy cases. This presentation reviews the various immunomodulators developed/investigated for this purpose. Among the various mycobacterial agents, BCG, BCG + M. leprae, Mycobacterium w, ICRC bacillus and M. vaccae have been tried in leprosy patients and varying degrees of beneficial effects on bacterial killing and clearance have been observed. Studies carried out at CJIL, Agra and elsewhere suggest an important role for these mycobacteria as immunotherapeutic agents. Other mycobacteria - M. habana, M. phlei, M. gordonae - have also been reported to be promising experimentally. In addition, various drugs such as levamisole, zinc and RACA 854 have been observed to have immunomodulatory role in leprosy cases. Other promising immunomodulators include transfer factor, interferon gamma, interleukin 2 and acetoacetylated M. leprae. The progress achieved shows that immunotherapy may be considered as adjunct to chemotherapy to enhance bacterial killing as well as bacterial clearance and thus may be recommended to shorten the treatment period, especially in bacilliferous leprosy cases.

Immune and nutritional recovery of severely malnourished children

Chevalier P.; Sevilla R.; Zalles L.; Sejas E.; Belmonte G.; Parent G.; Jambon B.
ORSTOM, Laboratoire de Nutrition Tropicale, BP 5045, 34032 Montpellier Cedex 2 France
Cahiers Sante (France), 1996, 6/4 (201-208)

In developing countries, more than 123 million children die each year from the combined effects of malnutrition and infection. Malnourished children have impaired cellular immunity and are particularly sensitive to opportunistic infections. However, immune recovery has rarely been investigated during nutritional rehabilitation. Indeed, mortality remains high during renutrition, and relapses are frequent. We established a center in Cochabamba, Bolivia, specifically to save these children by treating both clinical and nutritional problems and restoring immune function. The CRIN (center for immuno-nutritional recovery) admits children with severe malnutrition from the Cochabamba suburban area. They are from low income families, in crowded living conditions with poor sanitation and are weaned early. Nutritional diagnosis was based on weight-for-height, arm to head circumference ratio and clinical examination for edema, loss of subcutaneous tissue and diminished muscle mass. The children were examined daily and first treated for respiratory and intestinal infections. Sociological and psychological aspects were also included in our holistic approach to treating severe malnutrition. Children received a four-stage diet lasting 2 months. During the initial phase (1 week) they were given an oil-sugar-mild based diet, with half lactose concentration, seven times a day. This supplied 1.5 to 2.5 g of protein and 120 to 150 kcal/kg of body weight, according to the PEM pattern. Protein and energy intake was then slowly increased during the transition phase (1 week). During the next, 'calorific-protein bombing' phase (6 weeks) 5 g of protein and 200 kcal/kg of body weight were given daily, such that there was sufficient energy for protein accumulation. During the last, discharge phase (1 week), the protein and energy contents were slowly decreased. Weight, height, arm and head circumferences, and triceps skin-fold thickness were measured weekly by standardized methods. Thymus size was assessed weekly by mediastinal ultrasound scanning with a portable scanner (ALOKA SSD-210 DXII, Tokyo) using a 5 MHz linear pediatric probe. Lymphocyte subpopulations in peripheral blood were investigated monthly using monoclonal antibodies. Compared to controls, the malnourished group had severe involution of the thymus, a significantly higher proportion of circulating immature T lymphocytes and a lower proportion of mature T lymphocytes. The two month longitudinal study showed that normal anthropometric values (90% NCHS weight for height) were recovered after one month of rehabilitation. However, immune recovery (thymic area of 350 mm2) required two months. This may explain the frequent relapses among malnourished children discharged after one month on the basis of 'apparent nutritional health'. Such children may remain immunodepressed, and should therefore be considered as high risk children. To test an immunostimulatory treatment, we designed a historical cohort study of malnourished children who received 2 mg of zinc per day. The children were matched for age, sex, anthropometric criteria and nutritional status with malnourished control children (treated previously without zinc). Anthropometric recovery was obtained in both groups in one month. Children receiving zinc attained immunological recovery within one month, whereas children not receiving zinc took two months. Thus zinc hastened immunological recovery concomitant with nutritional recovery such that the duration of hospitalization could be halved: after one month of this immuno-nutritional treatment, malnourished children appear to be sufficiently healthy to face their pathogenic home environment.

Aspects of airway defence mechanisms

Korpas J.; Honda Y.
Department Pathophysiology, Jessenius Medical Faculty, Comenius University, Slabinska 26, 037 53 Martin Slovak Republic
Pathophysiology (Netherlands), 1996, 3/2 (81-86)

This review deals with recent findings in the airways and lung defence. It is well known that the respiratory tract forms the largest part of the human body surface which is directly exposed to the influence of inspired air. This can differ with regard to temperature, humidity, capacity of harmful gases, vapors, pollutants, and living and non-living particles. Therefore the airways and lungs have very effective defence processes consisting of reflex and non-reflex mechanisms. The reflex reactions include coughing, sneezing, aspiration and apnoeic reflexes, laryngo- and bronchospasms and mucociliary transport which has been considered to be a non-reflex reaction. The electrostatic filter of the tonsilar ring, immunological and antimicrobial defence, oxidant-antioxidant and protease-antiprotease systems and the architecture of the airways belong to the non-reflex group. Considerable progress has been made in understanding molecular mechanisms over the last decade. From this viewpoint the defence complex of activated pulmonary epithelial and inflammatory cells together with their mediators is very important. This complex has not previously been identified in the airways defence system. Both reflex and non-reflex mechanisms are independent units, but they normally interact. It is paradoxical that an original physiological defence activity can change its character into a pathological one if it is inadequate, survives the cause of its activation or triggers some secondary pathological process. In spite of intensive study of the respiratory tract defence systems in the last few years there are many links in structure and function which need further elucidation. Thus these large complexes of defence mechanisms require further study.

Cellular and humoral immunity in rats after gestational zinc or magnesium deficiency

Vormann J.; Michalski L.; Gunther T.
Freie Universitat, Inst. fur Molekularbiologie/Biochem., Arnimallee 22, D-14195 Berlin Germany
Journal of Nutritional Biochemistry (USA), 1996, 7/6 (327-332)

The effects of gestational Mg or Zn deficiency on the humoral or cellular immunity of newborn rats were investigated. Mg deficiency was induced by feeding a diet containing 180 ppm Mg from day 0 to day 21 of gestation and Zn deficiency was induced by feeding a diet containing 1.5 ppm Zn from day 0 to day 19. Controls were fed a diet with 1,000 ppm Mg and 100 ppm Zn from day 0 to day 21. Thereafter, all maternal rats and newborns were fed diets with normal amounts of Mg or Zn. Three and six weeks after birth, T-cell subpopulations in blood and thymus and B-cells in blood of the newborns were detected by flow cytometry. Plasma contents of IgG, IgM, and IgA were determined by radial immunodiffusion. Mg deficiency reduced litter size and pup weight. Three weeks after birth, the total number of leukocytes and lymphocytes in blood was significantly decreased, due to a reduction of T-helper and cytotoxic T-cells. Activated T-cells and B-cells were unchanged. Six weeks after birth, T-cell subpopulations approached controls values, whereas IgG content in plasma was slightly reduced. Gestational Zn deficiency reduced litter size and induced malformations. Three and six weeks after birth, body weight, number of leukocytes, lymphocyte, and T-cell subpopulations were not significantly changed. Plasma IgM was decreased 3 weeks after birth in correlation to the number of B-cells, which represented only 4% of total lymphocytes. These effects were repaired by the sixth week. Plasma IgG was reduced at 6 weeks. No effects on T-cell subpopulations in isolated thymocytes were detected after gestational Mg or Zn deficiency.

Immunomodulation by Pycnogenol (R) in retrovirus-infected or ethanol-fed mice

Cheshier J.E.; Ardestani-Kaboudanian S.; Liang B.; Araghiniknam M.; Chung S.; Lane L.; Castro A.; Watson R.R.
Dept. of Family/Community Medicine, University of Arizona, Tucson, AZ 85724 USA
Life Sciences (USA), 1996, 58/5 (PL-87-PL-96)

Pycnogenol (R) is a commercial mixture of bioflavonoids that exhibits antioxidative activity. The effects of dietary pycnogenol on immune dysfunction in normal mice as well as those fed ethanol or infected with the LP-BM5 murine retrovirus were determined. The ethanol consumption and retrovirus infection cause abnormalities in the function and/or structure of a broad array of cells involved in humoral and cellular immunity. Pycnogenol enhanced in vitro IL-2 production by mitogen-stimulated splenocytes if its production was suppressed in ethanol-fed or retrovirus-infected mice. Mitogenesis of splenocytes did not show a significant change in mice treated with pycnogenol. It reduced the elevated levels of interleukin-6 produced in vitro by cells from retrovirus infected mice and IL-10 secreted by spleen cells from mice consuming ethanol. Natural killer cell cytotoxicity was increased with pycnogenol treatment.

Iron in liver diseases other than hemochromatosis

Bonkovsky H.L.; Banner B.F.; Lambrecht R.W.; Rubin R.B.
Div. of Digestive Disease/Nutrition, Univ. of Massachusetts Med. Center, 55 Lake Avenue, North, Worcester, MA 01655 USA
Seminars in Liver Disease (USA), 1996, 16/1 (65-82)

There is growing evidence that normal or only mildly increased amounts of iron in the liver can be damaging, particularly when they are combined with other hepatotoxic factors such as alcohol, porphyrogenic drugs, or chronic viral hepatitis. Iron enhances the pathogenicity of microorganisms, adversely affects the function of macrophages and lymphocytes, and enhances fibrogenic pathways, all of which may increase hepatic injury due to iron itself or to iron and other factors. Iron may also be a co-carcinogen or promoter of hepatocellular carcinoma, even in patients without HC or cirrhosis. Based on this and other evidence, we hope that the era of indiscriminate iron supplementation will come to an end. Bloodletting, a therapy much in vogue 2 centuries ago, is deservedly enjoying a renaissance, based on our current understanding of the toxic effects of iron and the benefits of its depletion.

Viamin E supplementation induces an early recovery of cellular immunity decreased following X-ray irradiation

Moriguchi S.; Oonishi K.; Kishino Y.; Umegaki K.
Department of Nutrition, School of Medicine, University of Tokushima, Tokushima 770 Japan
Nutrition Research (USA), 1996, 16/4 (645-656)

We have previously reported that vitamin E has an ability to enhance T cell differentiation in rat thymus. The aim of this study is to investigate whether T cell differentiation enhanced by vitamin E supplementation is effective in decreasing cellular immunity after X-ray irradiation in rats. Male Fisher rats, 4-weeks old, were fed control (50 mg vitamin E/kg diet) or high vitamin E diet (585 mg vitamin E/kg diet) for 4 weeks and then irradiated X-ray. On 2, 5 and 9 days after X-ray irradiation, rats were killed under anesthesia and their cellular immune functions were assayed. Vitamin E supplementation did not result in decreased thymic weights or change in the numbers of thymocytes and peripheral blood lymphocytes (PBL) following X-ray irradiation. In addition, proliferation of PBL with T cell mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), also decreased in both control and high vitamin E groups following X-ray irradiation. On the contrary, proliferation of bone marrow cells (BMC) was maintained much the same as pretreatment of X-ray irradiation in high vitamin E group even after X-ray irradiation compared to a significant decrease in the control group. The proliferation of thymocytes with PHA or ConA also showed an early recovery in high vitamin E, which was associated with not the production of interleukin 2 (IL2), T cell growth factors, but early recovery in the proportion of CD4+CD8+ T cells in thymocyte. These results suggest that vitamin E supplementation accelerates the recovery of the X-ray irradiation- induced decrease in cellular immunity. The signs of accelerated recovery were enhanced T cell differentiation in thymus and the maintenance of bone marrow cell (BMC) proliferation during X-ray irradiation.

Effects of short-term zinc supplementation on cellular immunity, respiratory symptoms, and growth of malnourished Equadorian children

Sempertegui F.; Estrella B.; Correa E.; Aguirre L.; Saa B.; Torres M.; Navarrete F.; Alarcon C.; Carrion J.; Rodriguez A.; Griffiths J.K.
Inmunologia y Bioquimica, Facultad de Medicina, Universidad Central del Ecuador, PO Box 60, Sucursal 16 CEQ, Quite Ecuador
European Journal of Clinical Nutrition (United Kingdom), 1996, 50/1 (42-46)

Objective: To assess the effect of zinc supplementation on respiratory tract disease, immunity and growth in malnourished children. Design: A randomized double-blind placebo-controlled trial.

Setting: A day-care center in Quite, Ecuador.

Subjects: Fifty children (12-59 months old) recruited by height-for-age and weight-for-age deficit.

Interventions: Twenty-five children (supplemented, S group) received 10 mg/day of zinc as zinc sulfate, and 25 (nonsupplemented, NS group) received a placebo during 60 days. All were also observed during a 60-day postsupplementation period. Two children of the S group dropped out. Daily the clinical presence of cough, respiratory tract secretions, and fever, was recorded. On days 0, 60 and 120, the cutaneous delayed-type hypersensitivity (DTH) to multiple antigens, and anthropometric parameters were assessed. On days 0 and 60 serum zinc levels were also measured.

Results: On day 60, DTH was significantly larger (20.8 plus or minus 7.1 vs 16.1 plus or minus 9.7 mm), and serum zinc levels were significantly higher (118.6 plus or minus 47.1 vs 83.1 plus or minus 24.5 microg/dl) in the S group than in the NS group (P < 0.05 for each). The incidence of fever (relative risk (RR): 0.30, c.i. = 0.08-0.95, P = 0.02), cough (RR): 0.52, c.i. = 0.32-0.84, P = 0.004) and upper respiratory tract secretions (RR):0.72, c.i. = 0.59-0.88, P = 0.001) was lower in the S group than in the NS group at day 60. At the end of the postsupplementation observation period (day 120), the incidence of fever and upper respiratory tract secretions was the same in both the S and NS groups. The incidence of cough was higher at day 120 in the S group than in the NS group (RR): 2.28, c.i. = 1.37-3.83, P = 0.001).

Conclusions: This study supports a role for zinc in immunity, and immunity to respiratory infections, while pointing out the need for larger studies.

Selenium: a quest for better understanding.

Badmaev V; Majeed M; Passwater RA
Sabinsa Corporation, Piscataway, NJ, USA.
Altern Ther Health Med (United States) Jul 1996, 2 (4) p59-62, 65-7

Selenium is an essential trace element in nutrition for the prevention of disease in humans. Epidemiological studies indicate an association between low nutritional selenium status and increased risks of cardiomyopathy, cardiovascular disease, and carcinogenesis in various sites of the body. The role of selenium supplementation in the prevention and treatment of AIDS-related pathology has been considered. Selenoproteins discovered in mammalian cells may account for the essentiality of selenium in the body's antioxidant defense; thyroid hormone function; immune system function, particularly the cellular immunity; formation of sperm; and functioning of the prostate gland. The seleno-organic compounds, primarily L-(+)-selenomethionine, generally are recognized as safe and effective forms of selenium supplementation. The nutritionally recommended dose of elemental selenium is estimated at 50 to 200 mg per day. There is, however, increased discussion of a pharmacological dose of selenium, significantly higher than the nutritional dose of the microelement, to treat active conditions. One way of increasing the tissue levels of selenium is to combine its ingestible form with a nutrient bioavailability enhancing compound. (87 Refs.)

In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients.

See DM; Broumand N; Sahl L; Tilles JG
Department of Medicine, U.C. Irvine Medical Center, Orange 92668, USA.
Immunopharmacology (Netherlands) Jan 1997, 35 (3) p229-35

Extracts of Echinacea purpurea and Panax ginseng were evaluated for their capacity to stimulate cellular immune function by peripheral blood mononuclear cells (PBMC) from normal individuals and patients with either the chronic fatigue syndrome or the acquired immunodeficiency syndrome. PBMC isolated on a Ficoll-hypaque density gradient were tested in the presence or absence of varying concentrations of each extract for natural killer (NK) cell activity versus K562 cells and antibody-dependent cellular cytotoxicity (ADCC) against human herpesvirus 6 infected H9 cells. Both echinacea and ginseng, at concentrations > or = 0.1 or 10 micrograms/kg, respectively, significantly enhanced NK-function of all groups. Similarly, the addition of either herb significantly increased ADCC of PBMC from all subject groups. Thus, extracts of Echinacea purpurea and Panax ginseng enhance cellular immune function of PBMC both from normal individuals and patients with depressed cellular immunity.

Allium sativum (garlic) treatment for murine transitional cell carcinoma.

Riggs DR; DeHaven JI; Lamm DL
Department of Urology, West Virginia University School of Medicine, Morgantown 26506, USA.
Cancer (United States) May 15 1997, 79 (10) p1987-94

BACKGROUND: Currently, immunotherapy with Bacillus Calmette-Guerin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment-related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model.

METHODS: C3H/HeN mice were randomized prior to initiation of each experimental protocol. Mice received 1 x 10(3) MBT2 cells in 0.1 mL RPMI-1640, administered subcutaneously into the right thigh, on Day 0 of the experiment. AS was injected at the site of tumor transplantation on Day 1 and at 2- to 7-day intervals up to Day 28. To evaluate the effects of oral AS in this model, treatment was initiated 30 days prior to tumor inoculation and continued for 30 days after tumor inoculation. Animals in all experiments were followed for tumor incidence, tumor growth, and survival.

RESULTS: In the initial experiments, subcutaneous AS significantly reduced tumor volume compared with the saline control (P < 0.05). Unfortunately, treatment-related death was also observed, requiring reduction in the total dose of AS. Animals that received 5 weekly immunizations of AS (5 mg, 5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had significantly reduced tumor incidence, tumor growth, and increased survival when compared with animals that received the saline control. No treatment-related deaths were observed with this treatment schedule. To determine whether systemic AS administration might be effective, orally administered AS was tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of drinking water. Mice that received 50 mg oral AS had significant reductions in tumor volume (P < 0.05) when compared with animals that received the saline control, and mice that received 500 mg oral AS had significant reductions in both tumor volume and mortality (P < 0.05).

CONCLUSIONS: The significant antitumor efficacy of subcutaneous and oral AS warrants further investigation and suggests that AS may provide a new and effective form of therapy for transitional cell carcinoma of the bladder.

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Combination thymosin alpha 1 and lymphoblastoid interferon treatment in chronic hepatitis C

Rasi G; DiVirgilio D; Mutchnick MG; Colella F; Sinibaldi-Vallebona P; Pierimarchi P; Valli B; Garaci E
Istituto di Medicina Sperimentale, CNR-Roma, Italy.
Gut (England) Nov 1996, 39 (5) p679-83

BACKGROUND: Monotherapy for chronic hepatitis C using interferon (IFN) results in a very small proportion of patients exhibiting a sustained response. Clinical trials assessing the benefit of combination drug therapy may provide evidence of improved treatment response over that seen with single drug treatment. AIM: To assess the response in patients with chronic hepatitis C to one year of combination treatment: thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU thrice weekly.

PATIENTS AND METHODS: Fifteen patients with serum HCV RNA positive chronic hepatitis C were studied. Eleven patients were treatment naive and four had failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b. All patients were given combination T alpha 1 and L-IFN therapy for one year with a six month follow up period.

RESULTS: Six months after initiation of treatment seven patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA.

CONCLUSIONS: The results of this open label trial suggest that there may be a potential benefit to combining an immune modulator (T alpha 1) with an antiviral (IFN) in the treatment of chronic hepatitis C. Verification of the observations in this study require completion of a randomised controlled study.

Effective immunization against neuroblastoma using double-transduced tumor cells secreting GM-CSF and interferon-gamma.

Bausero MA; Panoskaltsis-Mortari A; Blazar BR; Katsanis E
Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.
J Immunother Emphasis Tumor Immunol (United States) Mar 1996, 19 (2) p113-24

Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector MFG-granulocyte-macrophage colony-stimulating factor (GM-CSF), to examine immune stimulation conferred by localized GM-CSF production. Expression of murine GM-CSF by neuro-2a (N-2a/GM) significantly reduced its tumorigenicity. Moreover, immunization of mice with irradiated N-2a/GM cells resulted in a significant protective effect against live tumor challenge 14 days later. Approximately 41% of mice immunized with irradiated N-2a/GM versus 0% of those vaccinated with irradiated parental tumor survived. Surviving mice were rechallenged after 50 days with wild-type neuro-2a or with the Sa1 syngeneic sarcoma to discern whether the generated immunity was durable and tumor specific. All mice survived wild-type neuro-2a challenge, whereas none survived inoculation with Sa1. Because both CD4+ and CD8+ T cells were necessary during priming to this MHC class Ilo, II-tumor, these data indicate that major histocompatibility complex (MHC) class I+, II+ antigen-presenting cells (APCs) were required for the T-cell antitumor response. Co-expression of GM-CSF and IFN-gamma, both of which have immunostimulatory activities on antigen-presenting cells, abrogated the tumorigenic potential of this tumor and increased immunogenicity over N-2a/IFN but not N-2a/GM. Vaccination of mice with preexisting retroperitoneal tumors with irradiated N-2a/GM and irradiated N-2a/IFN/GM improved survival. There was a trend for nonirradiated transduced cells to be more immunogenic than their irradiated counterparts. Immunohistochemistry of tissues from the vaccination site revealed a pronounced macrophage infiltration associated with nonirradiated N-2a/GM and N-2a/IFN/GM. These data suggest that vaccination involving nonirradiated neuroblastoma cells transduced with genes that stimulate APCs may be a useful approach in stimulating antitumor T-cell responses.

Improved sustained response following treatment of chronic hepatitis C by gradual reduction in the interferon dose.

Shiffman ML; Hofmann CM; Luketic VA; Sanyal AJ; Contos MJ; Mills AS
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Hepatology (United States) Jul 1996, 24 (1) p21-6

Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with a high rate of relapse. IFN is thought to exert its effect against HCV via direct viral inhibition and immune stimulation. We have hypothesized that relapse following termination of therapy results from the sudden withdrawal of this immune modulatory effect and that gradual reduction in the IFN dose may decrease the incidence of relapse. One hundred six patients with chronic HCV were enrolled into this 24-month controlled, randomized prospective trial. All were treated with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who achieved biochemical response were randomized to either stop or taper IFN gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all three times a week). 0.5 mU twice weekly and then once weekly. Liver histology was assessed by Knodell index and HCV RNA was measured by a quantitative polymerase chain reaction (PCR) assay. Of the 92 patients who completed the initial 6 months of IFN treatment, 47 (51%) achieved biochemical response. Twenty-one of these patients were randomized to stop IFN treatment and 25 to taper (1 drop-out). At randomization patients were well matched with respect to age, sex, race, serum alanine transaminase (ALT), and liver histology. Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN treatment compared with only 60% who tapered IFN (P= .04). Virological relapse occurred in 90% of patients who stopped and only 48% of persons who tapered IFN therapy. At completion of the 24-month study patients who achieved long-term sustained biochemical response had a significantly lower mean Knodell score (3.5 vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85% vs. 18%) compared with relapsers. We conclude that gradual reduction in IFN dose is associated with a significant higher rate of sustained response and clearance of HCV RNA from serum compared with abruptly stopping treatment. This in turn is associated with a significant improvement in hepatic histology supporting the premise that response to IFN therapy can prevent progression to cirrhosis.

Improved immunotherapy of a recombinant carcinoembryonic antigen vaccinia vaccine when given in combination with interleukin-2.

McLaughlin JP; Schlom J; Kantor JA; Greiner JW
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Cancer Res (United States) May 15 1996, 56 (10) p2361-7

Interleukin-2 (IL-2) has been an effective immune modulator in several active-specific immunotherapy experimental protocols using either viral or oncolysate-based vaccines. In this report, data indicate that IL-2 administration can appreciably augment the therapeutic effect of a single immunization of a recombinant vaccinia virus-carcinoembryonic antigen (rV-CEA) vaccine using a CEA-expressing syngeneic experimental murine model system. A single rV-CEA immunization of C57BL/6 mice bearing palpable CEA-positive colon adenocarcinoma tumors results in complete tumor regression in approximately 20% of the mice. The addition of a course of low-dose IL-2 results in complete tumor regression in 60-70% of the mice. Moreover, the combination of rV-CEA and IL-2 induces systemic immunity, which protects those tumor-free mice from subsequent rechallenge with the CEA-expressing tumor cells. No such tumor regression or protection was observed in those mice immunized with the wild-type vaccinia vaccine (V-Wyeth) alone or with IL-2 administration alone. Cellular immune assays revealed that the addition of IL-2 to rV-CEA immunization significantly increased the CEA-specific T-cell proliferative responses as well as the cytolytic T-cell responses when compared with rV-CEA immunization alone. The enhanced CEA-specific immune response, coupled with the improved experimental therapeutic outcome following IL-2 administration, suggests that treatment with that cytokine may effectively substitute for multiple rV-CEA immunizations in active-specific immunotherapy clinical protocols directed at CEA-expressing tumors.

Vitamins and immunity: II. Influenceof L-carnitine on the immune system.

De Simone C; Ferrari M; Lozzi A; Meli D; Ricca D; Sorice F
Acta Vitaminol Enzymol (Italy) 1982, 4 (1-2)

Vitamin A affects the antibody responses and may affect phagocytic function and properdin levels. Pyridoxine deficiency impairs nucleic acid synthesis and depresses antibody formation, delayed hypersensitivity reactions and the ability of phagocytes to kill bacteria. Pantothenic acid deficiency impairs antibody formation. Vitamin-C deficiency increases the incidence of infection, primary by a negative influence on reparative processes. Deficiencies of other vitamins either have not been sufficiently studied or have a variable effect. Moreover, even substances which for their biosynthesis require an adequate vitamin supplementation may exert immunomodulatory influences. With this respect the authors report their results on the influence of L-carnitine on the immune system. L-carnitine increases the proliferative responses of both murine and human lymphocyte following mitogenic stimulation and increase polymorphonuclear chemotaxis. Furthermore, L-carnitine, even at minimal concentrations, neutralizes the lipid induced immunosuppression.

Suppression of tumor growth and enhancement of immune status with high levels of dietary vitamin B6 in BALB/c mice.

Gridley DS; Stickney DR; Nutter RL; Slater JM; Shultz TD
J Natl Cancer Inst 1987 May;78(5):951-9

Effects of dietary vitamin B6 at levels ranging from deficiency to megadoses on the development of herpes simplex virus type 2-transformed (H238) cell-induced tumors and on in vitro responses relating to cell-mediated immunity were examined. Male BALB/cByJ mice (n = 260), 5 weeks of age, were fed 20% casein diets containing pyridoxine (PN) at 0.2, 1.2 for the control diet, 7.7, or 74.3 mg/kg diet for 4-11 weeks. After 4 weeks of dietary treatment, 120 of the mice received an injection of H238 cells; mice without H238 injection served as controls. At 4, 8, and 11 weeks, animals from each group were euthanized and blood and spleen samples obtained. Mice fed 0.2 mg PN developed mild deficiency symptoms and gained significantly less weight than those fed 1.2-, 7.7-, and 74.3-mg PN diets. Thirteen to 16 days after tumor cell injection, primary tumor incidence was lowest in mice fed 74.3 mg PN; later, incidence among groups was similar. Mice fed 1.2 mg PN had the largest primary tumor volume, the highest incidence of lung metastases, and the greatest number of metastatic nodules per animal at 7 weeks post injection. Overall, lower tumor volumes were found in animals fed 7.7 and 74.3 mg PN (14 and 32% less than the tumor volume for those fed 1.2 mg PN, respectively); mice fed 0.2 mg PN had the lowest tumor volume. Blood and spleen lymphoproliferative response to stimulation by phytohemagglutinin or concanavalin A generally tended to be higher in mice fed 7.7 and 74.3 mg PN as compared to that in animals fed either 0.2 or 1.2 mg PN. However, decreased mitogen-stimulated responsiveness was observed in all animals with progressive tumor growth. Tumor growth also resulted in splenomegaly and increased thymic atrophy. Significant negative relationships between tumor volume and tumor pyridoxal 5-phosphate (PLP) concentrations were observed for 1.2-, 7.7-, and 74.3-mg PN diet groups. These data suggest that high dietary intake of vitamin B6 may have suppressed tumor development by either immune enhancement or PLP growth regulation of this tumor.

The activities of coenzyme Q10 and vitamin B6 for immune responses.

Folkers K, Morita M, McRee J Jr
Institute for Biomedical Research, University of Texas, Austin 78712.
Biochem Biophys Res Commun 1993 May 28;193(1):88-92

Coenzyme Q10 (CoQ10) and vitamin B6 (pyridoxine) have been administered together and separately to three groups of human subjects. The blood levels of CoQ10 increased (p < 0.001) when CoQ10 and pyridoxine were administered together and when CoQ10 was given alone. The blood levels of IgG increased when CoQ10 and pyridoxine were administered together (p < 0.01) and when CoQ10 was administered alone (p < 0.05). The blood levels of T4-lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.01) and separately (p < 0.001). The ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.001) and separately (p < 0.05). These increases in IgG and T4-lymphocytes with CoQ10 and vitamin B6 are clinically important for trials on AIDS, other infectious diseases, and on cancer.

Research on coenzyme Q10 in clinical medicine and in immunomodulation.

Folkers K; Wolaniuk A
Drugs Exp Clin Res (Switzerland) 1985, 11 (8) p539-45

Coenzyme Q10 (CoQ10) is a redox component in the respiratory chain. CoQ10 is necessary for human life to exist; and a deficiency can be contributory to ill health and disease. A deficiency of CoQ10 in myocardial disease has been found and controlled therapeutic trials have established CoQ10 as a major advance in the therapy of resistant myocardial failure. The cardiotoxicity of adriamycin, used in treatment modalities of cancer, is significantly reduced by CoQ10, apparently because the side-effects of adriamycin include inhibition of mitochondrial CoQ10 enzymes. Models of the immune system including phagocytic rate, circulating antibody level, neoplasia, viral and parasitic infections were used to demonstrate that CoQ10 is an immunomodulating agent. It was concluded that CoQ10, at the mitochondrial level, is essential for the optimal function of the immune system.

Immunoenhancing effect of flavonoid compounds on lymphocyte proliferation and immunoglobulin synthesis.

Brattig NW; Diao GJ; Berg PA
Int J Immunopharmacol (England) 1984, 6 (3) p205-15

Flavonoid compounds are lipophilic agents which can interact with membrane lipids and may affect responsiveness of immune cells. We therefore studied whether cianidanol ((+)-catechin), the O-methyl-derivative (+)-3-methoxy-5,7,3',4'-tetrahydroxyflavan and palmitoyl-derivative (+)-3-palmitoyl-5,7,3',4'-tetrahydroxyflavan influence T and B cell functions. In addition, immunomodulatory property of ubiquinone 50 was also investigated. As controls were used cyclosporin A and inosine which are known to inhibit or enhance immune responses, respectively. The in vitro spontaneous, antigen and mitogen induced proliferation as well as immunoglobulin synthesis of peripheral blood mononuclear cells from healthy individuals was determined in the presence of different concentrations of the agents. All flavonoid compounds and ubiquinone 50 significantly increased (p less than 0.05 - less than 0.01) the spontaneous lymphocyte transformation but hardly affected antigen, alloantigen and mitogen induced proliferative response. Only cianidanol and O-methyl-derivative enhanced significantly (p less than 0.05 - less than 0.01) spontaneous, pokeweedmitogen and Staphylococcus aureus Cowan I induced immunoglobulin synthesis while the palmitoyl-derivative and ubiquinone 50 had only minor influence on B cell function. In contrast, Staphylococcus aureus induced immunoglobulin production was neither increased by inosine nor suppressed by cyclosporin A. These studies show that especially cianidanol and the O-methyl-derivative can exert an immunoenhancing effect on T and B cell functions.

Immunological senescence in mice and its reversal by coenzyme Q10.

Bliznakov EG
Mech Ageing Dev 1978 Mar;7(3):189-97

A pronounced suppression of the humoral, hemolytic, primary immune response in old (22 months) mice was demonstrated as compared with this response in young (10 weeks) mice. The suppression is associated with a lower thymus weight:body weight ratio. In contrast, the ratios spleen weight:body weight and liver weight:body weight in 10 weeks and 22 months old mice remain almost constant. A single administration of coenzyme Q10--a non-toxic, non-specific stimulant of the host defense system--partly compensates the age-determined suppression of the humoral, immune response. This suppression probably results from an age-dependent imbalance of T cells: B cells ratio and a decline of their immunological responsiveness which is compensated by the administration of coenzyme Q10.

Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients.

Lissoni P; Brivio F; Brivio O; Fumagalli L; Gramazio F; Rossi M
J Biol Regul Homeost Agents (Italy) Jan-Mar 1995, 9 (1) p31-3

Surgery-induced immunosuppression could influence tumor/host interactions in surgically treated cancer patients. Previous studies have shown that high-dose IL-2 preoperative therapy may neutralize surgery-induced lymphocytopenia. Moreover, experimental studies have demonstrated that the immunomodulating neurohormone melatonin (MLT) may amplify IL-2 activity and reduce its dose required to activate the immune system. On this basis, we have compared the immune effects of presurgical therapy with high-dose IL-2 with respect to those obtained with preoperative neuroimmunotherapy consisting of low-dose IL-2 plus MLT. The study included 30 patients with gastrointestinal tract tumors, who were randomized to undergo surgery alone, or surgery plus a preoperative biotherapy with high-dose IL-2 (18 million IU/day subcutaneously for 3 days) or low-dose IL-2 (6 million IU/day subcutaneously for 5 days) plus MLT (40 mg/day orally). Patients underwent surgery within 36 hours from IL-2 interruption. Both IL-2 plus MLT were able to prevent surgery-induced lymphocytopenia. However, mean number of lymphocytes, T lymphocytes and T helper lymphocytes observed on day 1 of postoperative period was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. Moreover, toxicity was less in patients treated with IL-2 and MLT. This biological study shows that both immunotherapy with high-dose IL-2 or neuroimmunotherapy with low-dose IL-2 plus MLT preoperatively are tolerated biotherapies, capable of neutralizing surgery-induced lymphocytopenia in cancer patients. Moreover, the study would suggest that the neuroimmunotherapy may induce a more rapid effect on postoperative immune changes with respect to IL-2 alone.

Pineal-opioid system interactions in the control of immunoinflammatory responses.

Lissoni P, Barni S, Tancini G, Fossati V, Frigerio F
Division of Radiation Oncology, San Gerardo Hospital, Monza, Milan, Italy.
Ann N Y Acad Sci 1994 Nov 25;741:191-6

Several studies have demonstrated involvement of the pineal gland in the regulation of neuropeptide secretion and activity. In particular, the existence of links between the pineal gland and the brain opioid system has been documented. Both opioid peptides and melatonin (MLT), the most investigated pineal hormone, play an important role in neuromodulation of the immunity. Moreover, the immune effects of MLT are mediated by endogenous opioid peptides, which may be produced by both the endocrine system and the immune cells. In addition, the immune dysfunctions that characterize some human diseases, such as cancer, depend not only on the immune system per se, but also at least in part, on altered secretion of immunomodulating neurohormones, including MLT and opioid peptides. Therefore, the exogenous administration of neurohormones could potentially improve the immune status in humans. The present study evaluates the effects of MLT on changes in the number of T lymphocytes, natural killer cells, and eosinophils induced by exogenous administration of interleukin-2 (IL-2). Macrophage activity was also evaluated by determining serum levels of its specific marker, neopterin. The study was performed in 90 patients with advanced solid neoplasms, who received IL-2 at a dose of 3 million IU/day subcutaneously for 6 days a week for 4 weeks plus MLT at a daily dose of 40 mg. Both drugs were given in the evening. The results were compared to those in 40 cancer patients treated with IL-2 alone. The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those who received IL-2 alone.

Evidence for a direct action of melatoninon the immune system.

Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF
Department of Physiology, University of Hong Kong.
Biol Signals 1994 Mar-Apr;3(2):107-17

Pineal melatonin modulates the mammalian immune system. In vivo studies showed that melatonin enhanced the natural and acquired immunity while in vitro studies demonstrated its inhibitory influence. The mechanism of melatonin action on the immune system remains unknown. Actions through lymphokines or opioid release or via other endocrine changes have been proposed. In this paper, a direct action of melatonin on the lymphoid tissue is hypothesized. 2-[125I]Iodomelatonin binding sites have been identified in the membrane homogenates of thymus, bursa of Fabricius and spleens of a number of birds and mammals. The bindings were stable, saturable, reversible, specific and of high affinity. The Bmax ranged from 0.6 to 3.9 fmol/mg protein. The Kd was in the physiological range of circulating melatonin levels, about 30-70 pmol/l. The binding sites in the primary lymphoid organs demonstrated diurnal variation in density, with higher levels found at the middle of the light period. However, those in the spleen did not vary with the time of the day.An age-dependent decrease in the density was also found in the chicken bursa of Fabricius. In addition, when the nocturnal melatonin secretion was suppressed by constant light exposure, the density of the binding sites increased in the guinea pig spleen. Immunosuppression with cortisol injection in young ducks decreased the density of the melatonin binding sites in the thymus. The regulation of the binding characteristics by physiological variation in melatonin levels and/or immunological status of the animals provide evidence that these 2-[125I]iodomelatonin binding sites in the lymphoid tissues may be physiologically significant and represent true melatonin receptors. The melatonin receptors in the lymphoid organs may be coupled to a G protein as Guanosine 5'-0-(3-thiotriphosphate inhibited 2-[125I]iodomelatonin binding in the spleen by increasing the Kd and decreasing the Bmax.

The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice.

Mocchegiani E, Bulian D, Santarelli L, Tibaldi A, Muzzioli M, Pierpaoli W, Fabris N
Gerontology Research Department, Italian National Institute for Research on Aging (INRCA), Ancona.
J Neuroimmunol 1994 Sep;53(2):189-201

It has been demonstrated that melatonin, the main neuro-hormone of the pineal gland, affects thymic functions and the regulation of the immune system. In addition, experimental evidences indicate that melatonin can modulate zinc turnover. The knowledge that with advancing age both melatonin and zinc plasma levels decline, and that zinc supplementation in old mice is able to restore the reduced immunological functions, has prompted investigations on the effect of chronic melatonin treatment or pineal graft in old mice on the age-related decline of thymic endocrine activity, peripheral immune functions and zinc turnover. Both melatonin treatment in old mice and pineal graft into the thymus of old mice correct the reduced thymic endocrine activity and increase the weight of the thymus and its cellularity. A restoration of cortical thymic volume, as detected by the percentage of tissue in active proliferation, is also observed in old mice after both treatments. Thymocyte CD phenotype expression is also restored to young values. At peripheral level, recovery of peripheral blood lymphocyte number and of spleen cell subsets, with increased mitogen responsiveness also occurs. Melatonin treatment or pineal graft induce also a restoration of the altered zinc turnover in aged mice with an increment of the crude zinc balance from negative (-1.6 microgram/day/mouse) to positive value (+1.2 microgram/day/mouse), similar to that one of young mice (+1.4 microgram/day/mouse). The reduced zinc plasma level is restored to normal values. These findings support the idea that the effect of melatonin on thymic endocrine activity and peripheral immune functions may be mediated by the zinc pool.

The immunoneuroendocrine role of melatonin.

Maestroni GJ
J Pineal Res (Denmark) Jan 1993, 14 (1) p1-10

A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MIIO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as gamma-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.

The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties.

Maestroni GJ, Conti A
Laboratory for Experimental Pathology, Istituto Cantonale di Patologia, Locarno, Switzerland.
J Neuroimmunol 1990 Jul;28(2):167-76

In previous studies we showed that in mice the pineal gland modulates the immune response via the circadian synthesis and release of melatonin. Exogenous melatonin proved also to exert immunoenhancing effects and to counteract completely the immunologic effect of acute stress. Melatonin was active only in vivo, in mice primed with T-dependent antigens and its effects on the primary antibody response and thymus weight were abolished by the specific opioid antagonist naltrexone. Here we demonstrate that physiologic concentrations of melatonin stimulate, in vitro, activated L3T4+ (CD4+) cells to release opioid agonist(s) that can reproduce in vivo the immunoenhancing and anti-stress effects on thymus cellularity and antibody production of melatonin and compete with specific binding of [3H]naloxone to mouse brain membranes. Similar results were obtained when mitogen-activated human immunocompetent cells were incubated with melatonin. In the human model the results were, however, less consistent than those obtained with murine cells, in that only four out of ten blood donors provided cells that were responsive to melatonin. This finding elucidates the mechanism of a novel immuno-neuroendocrine connection with relevant implications for our understanding of the neuroendocrine factors that may influence the immune response in vivo in normal and stressful situations. In addition, it opens new perspectives in a wide range of research fields.

Endocrine and immune effects of melatonin therapy in metastatic cancer patients.

Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F
Divisione di Radioterapia Oncologica, Ospedale San Gerardo, Milano, Italy.
Eur J Cancer Clin Oncol 1989 May;25(5):789-95

Melatonin, the most important indole hormone produced by the pineal gland, appears to inhibit tumor growth; moreover, altered melatonin secretion has been reported in cancer patients. Despite these data, the possible use of melatonin in human neoplasms remains to be established. The aim of this clinical trial was to evaluate the therapeutic, immunological and endocrine effects of melatonin in patients with metastatic solid tumor, who did not respond to standard therapies. The study was carried out on 14 cancer patients (colon, six; lung, three; pancreas, two; liver, two; stomach, one). Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period in an oral dose of 10 mg daily in patients who had a remission, stable disease or an improvement in PS. Before and after the first 2 months of therapy, GH, somatomedin-C, beta-endorphin, melatonin blood levels and lymphocyte subpopulations were evaluated. A partial response was achieved in one case with cancer of the pancreas, with a duration of 18+ months; moreover, six patients had stable disease, while the other eight progressed. An evident improvement in PS was obtained in 8/14 patients. In patients who did not progress, T4/T8 mean ratio was significantly higher after than before melatonin therapy, while it decreased in patients who progressed. On the contrary, hormonal levels were not affected by melatonin administration. This study would suggest that melatonin may be of value in untreatable metastatic cancer patients, particularly in improving their PS and quality of life; moreover, based on its effects on the immune system, melatonin could be tested in association with other antitumor treatments.

Dehydroepiandrosterone (DHEA) treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection.

Danenberg HD; Ben-Yehuda A; Zakay-Rones Z; Friedman G
Vaccine (England) 1995, 13 (15) p1445-8

Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity. Recently it was suggested that its age-associated decline is related with immunosenescence. To examine whether DHEA administration could effectively reverse the age-associated decline of immunity against influenza vaccine, aged mice were simultaneously vaccinated and treated with DHEA. Reversal of the age-associated decline and a significant constant increase of humoral response was observed in treated mice. Increased resistance to post-vaccination intranasal challenge with live influenza virus was observed in DHEA-treated aged mice. Thus, DHEA treatment overcame the age-related defect in the immunity of old mice against influenza.

Dehydroepiandrosterone modulationof lipopolysaccharide-stimulated monocyte cytotoxicity.

McLachlan JA, Serkin CD, Bakouche O
Department of Molecular Pharmacology and Biologic Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA.
J Immunol 1996 Jan 1;156(1):328-35

Dehydroepiandrosterone (DHEA), the predominant androgen secreted by the adrenal cortex, can be converted to both potent androgens and estrogens. In addition to its role as a precursor for other steroid hormones, DHEA has been proposed to play an important role in immunity. This study has investigated DHEA modulation of LPS-induced monocyte cytotoxicity. Cytotoxicity markers assessed include tumor cell killing, IL-1 secretion, reactive oxygen intermediate release, nitric oxide synthetase activity as measured by the release of reactive nitrogen intermediates, complement receptor-1 cell surface protein, and TNF-alpha protein presence. Monocytes stimulated with LPS concentrations of 1.0 micrograms/ml displayed the above cytotoxic markers, whereas monocytes stimulated with DHEA alone or with LPS at a lower concentration of 0.2 ng/ml did not. However, when used simultaneously, DHEA and LPS 0.2 ng/ml displayed a synergistic effect on monocyte cytotoxicity protein, and TNF-alpha cancerous cell lines, IL-1 secretion, reactive nitrogen intermediate release, complement receptor-1 cell-surface protein, and TNF-alpha protein to levels comparable with levels obtained using LPS 1.0 microgram/ml. Finally, Scatchard plot analysis demonstrated the presence of a DHEA receptor in monocytes, suggesting that DHEA effects on LPS-stimulated monocytes are mediated through a receptor-dependent process.

Administration of dehydroepiandrosterone reverses the immune suppression induced by high dose antigen in mice.

Kim HR, Ryu SY, Kim HS, Choi BM, Lee EJ, Kim HM, Chung HT
Department of Microbiology/Immunology, School of Medicine, College of Oriental Medicine, Wonkwang University, Iri, Chonbuk, Korea.
Immunol Invest 1995 May;24(4):583-93

Several factors including antigen concentration, the route of antigen administration, hormones and cytokines have shown to affect T cells to produce the distinct patterns of lymphokines which exert regulatory and effector functions of immune response. In this study, we asked whether administration of dehydroepiandrosterone (DHEA) to mice which were tolerized by high dose of antigen could modulate T cell functions to restore the suppressed cellular immune response and to produce the distinct lymphokines. An intravenous injection of high dose of sheep red blood cells induced suppression of delayed type hypersensitivity (DTH) and a single subcutaneous injection of the tolerant mice with DHEA restored the suppressed DTH response. Furthermore, in vitro treatment of spleen cells from tolerant mice with DHEA abolished the transfer of tolerance to naive recipients. Lymphocytes from the DHEA-treated tolerant mice produced more IFN-gamma and less IL-4 and IL-6 than the cells from tolerant animals without DHEA treatment. These findings indicate that DHEA could recover antigen-specific immune suppression by differentially affecting T cells to produce the distinct lymphokines.

Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice.

Morfin R, Courchay G
Bio-industries, Laboratoire de Biologie, Conservatoire National des Arts et Metiers, Paris, France.
J Steroid Biochem Mol Biol 1994 Jul;50(1-2):91-100

Dehydroepiandrosterone (DHEA) and pregnenolone (PREG) were both metabolized by homogenates of brain, spleen, thymus, perianal skin, ventral skin, intestine, colon, coecum and muscle tissues from mice. The use of 2H-labeled substrates and of the twin ion technique of gas chromatography-mass spectrometry permitted identification of 7 alpha-hydroxy-DHEA and of 5-androstene-3 beta, 17 beta-diol as DHEA metabolites in digests of all tissues. The extent of PREG metabolism was much lower than for DHEA with all tissues but amounts of the main transformation product were sufficient in brain, spleen and ventral skin digests for identification with 7 alpha-hydroxy-PREG. Dimethylsulfoxide (DMSO) solutions of DHEA, PREG and of their 7-hydroxylated metabolites were injected at different doses and time intervals prior to proximal subcutaneous administration of a lysozyme antigen. Quantities of anti-lysozyme IgG were measured in the serum of treated mice and compared with that from sham-treated animals. Increase of anti-lysozyme IgG was obtained with DHEA and PREG (1 g/kg) when injected 2 h prior to lysozyme. Much lower doses (160 times less) of 7 alpha-hydroxy-DHEA and -PREG were also found to be significantly active when administered at the moment of lysozyme injection. A larger dose of 7 beta-hydroxy-DHEA (50 mg/kg) was necessary for a similar effect. These results suggest that in tissues where immune response takes place, the locally-produced 7-hydroxy metabolites of PREG and DHEA are involved in a process which may participate in the physiological regulation of the body's immune response.

The relationship of serum DHEA-S and cortisol levels to measures of immune function in human immunodeficiency virus-related illness.

Wisniewski TL, Hilton CW, Morse EV, Svec F
Department of Medicine, Louisiana State University Medical Center, New Orleans.
Am J Med Sci 1993 Feb;305(2):79-83

Human immunodeficiency virus (HIV) is a major cause of immunoincompetence. Whether the virus, itself, accounts for all the deficiency remains in question. Steroids can also influence immune function; glucocorticoids cause immunoincompetence while dehydroepiandrosterone (DHEA) enhances immune function. Changes in the levels of such hormones during the course of HIV illness might result in significant changes in immune competence. The purpose of this study is to investigate whether dehydroepiandrosterone-sulphate (DHEA-S) or cortisol levels correlate with absolute CD4 lymphocyte levels. Plasma for cortisol and DHEA-S was drawn from 98 adults with HIV. Of these, 67 had simultaneous CD4 levels. Cortisol levels were 12.4 +/- 4.6 micrograms/dl, DHEA-S 262 +/- 142 micrograms/dl, and CD4 levels were 308 +/- 217/mm3 (mean +/- SD). Correlational analysis revealed a significant relationship between DHEA-S and CD4 levels (r = 0.30; p = 0.01) but not between CD4 levels and cortisol (r = 0.11; p = 0.36) or cortisol/DHEA-S ratios (r = 0.17; p = 0.16). When analyzed by clinical subgroups, significant differences were also found with a decrease in DHEA-S levels seen in persons with more advanced illness. The data exhibit a positive relationship between the immune status of patients with HIV-related illness and DHEA, leading to the hypothesis that DHEA deficiency may worsen immune status.

Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells.

Suzuki T, Suzuki N, Daynes RA, Engleman EG
Department of Pathology, Stanford University School of Medicine, California 94305.
Clin Immunol Immunopathol 1991 Nov;61(2 Pt 1):202-11

Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it is well established that DHEA serves as an intermediate in sex steroid synthesis, recent studies in mice suggest that DHEA may also be a physiologic regulator of IL2 secretion. To explore the effect of DHEA on the human immune system, T lymphocytes from healthy adults were exposed to DHEA followed by stimulation with mitogens or antigen. Upon activation with a variety of stimuli, T cells pretreated with 10(-8) to 10(-11) M DHEA produced significantly greater amounts of IL2 and mediated more potent cytotoxicity than T cells activated in the absence of this steroid hormone. The peak effect of DHEA was observed at 10(-9) M, the concentration of hormone present in the blood of normal adults. In contrast to its effect on murine T cells, the IL2 enhancing effect of DHEA on human lymphocytes was limited to fresh CD4+ T cells and CD4+ clones; neither fresh CD8+ cells nor CD8+ clones were directly affected by DHEA treatment, although CD8+ cells stimulated in the presence of CD4+ cells and DHEA demonstrated enhanced cytotoxicity. The enhancing effect of DHEA was also detected at the level of IL2 mRNA, suggesting that DHEA may act as a transcriptional enhancer of the IL2 gene in CD4+ T cells. These results corroborate and extend earlier studies in mice and suggest a physiologic role for DHEA in regulating the human immune response.

Protection from glucocorticoid induced thymic involution by dehydroepiandrosterone.

May M, Holmes E, Rogers W, Poth M
Walter Reed Army Medical Center, Washington, D.C. 20307-5001.
Life Sci 1990;46(22):1627-31

Dehydroepiandrosterone (DHEA), the most abundantly secreted human adrenal steroid, has no known specific function. In spite of this fact there is an abundance of data associating DHEA with "health" in both man and experimental animals. Research in our laboratory has demonstrated evidence for an antagonistic interaction between DHEA and glucocorticoids (GC) in liver and brown adipose tissue. We hypothesized that DHEA also antagonized effects of GC on the immune system and that this "immune protective effect" might explain the diffuse positive effects of DHEA reported in the literature. Effects of GC on the immune system include involution of the thymus when given in animals in vivo and death of thymic lymphocytes in vivo with exposure to these steroids. We hypothesized that DHEA would block this GC mediated thymocyte destruction in vivo and in vitro. Pretreatment with DHEA for three days blocked approximately 50% of the thymic involution seen with dexamethasone. Results of in vitro experiments confirmed protective effects of DHEA in pretreated animals. (less than 50% of cell death in lymphocytes from pretreated mice compared with lymphocytes from control mice.) We conclude from these studies that DHEA protects against at least one GC anti-immune effect, thymic lymphocyte lysis.

Immune development in young-adult C.RF-hyt mice is affected by congenital and maternal hypothyroidism.

Erf GF
Department of Biological Sciences, Smith College, Northampton, Massachusetts 01063.
Proc Soc Exp Biol Med 1993 Oct;204(1):40-8

C.RF-hyt mice carry a mutation (hyt) that results in the phenotypic expression of congenital hypothyroidism in hyt/hyt mice due to a nonresponsiveness of the thyroid gland to thyroid-stimulating hormone. Heterozygotes of this strain are euthyroid. To further define thyroid-immune interactions, the effect of congenital hypothyroidism and maternal hypothyroidism on immune development were examined in 3- to 4-month-old hyt/+ and hyt/hyt progeny from hyt/+ and hyt/hyt dams. The state of immune development in these mice was compared on the basis of immune organ weights and the proliferation response of splenocytes stimulated with the T cell mitogens concanavalin A (Con A) and phytohemagglutinin and the B cell mitogen lipopolysaccharide. In addition, analysis of T cell subpopulations in thymus and spleen was conducted using direct and indirect immunofluorescence and flow cytometry. Data analyses for the main effects of congenital hypothyroidism on immune development revealed a significantly lower absolute thymus weight (P < 0.001), a lower (P = 0.022) percentage of thymocytes expressing CD8 (CD8+), a higher (P = 0.010) ratio between CD4+ and CD8+ thymocytes, a lower (P < 0.001) absolute and adjusted spleen weight, a lower (P = 0.001) Con A to phytohemagglutinin response ratio, a higher (P = 0.003) percentage of CD4+ splenocytes, and a marginally significant (P = 0.055) increase in the ratio between CD4+ and CD8+ splenocytes in hypothyroid compared with euthyroid mice. Data analyses for the main effects of maternal hypothyroidism revealed a significantly higher absolute (P = 0.025) and adjusted (P = 0.001) thymus weight, a higher (P = 0.006) ratio between CD4+ and CD8+ thymocytes, a lower Con A (P = 0.018) and lipopolysaccharides (P < 0.001) response, a marginally (P = 0.069) lower Con A to phytohemagglutinin response ratio, a lower (P = 0.001) percentage of CD4+ splenocytes, and a lower (P = 0.003) ratio between CD4+ and CD8+ splenocytes in progeny of hypothyroid compared with progeny of euthyroid mothers. These data provide further evidence for the importance of normal thyroid function in the development, maintenance, and function of the immune system. It was concluded that not only congenital hypothyroidism results in altered immune development in young-adult mice, but also long-term effects on immune development occur in progeny of hypothyroid mothers.

Binding and functional effects of thyroid stimulating hormone on human immune cells.

Coutelier JP, Kehrl JH, Bellur SS, Kohn LD, Notkins AL, Prabhakar BS
Laboratory of Oral Medicine, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Immunol 1990 Jul;10(4):204-10

The expression and functional relevance of thyroid stimulating hormone (TSH) receptors on human immune cells were studied. Flow cytometric analysis was used to study the binding of biotinylated TSH to human peripheral blood mononuclear cells (PBMC) and various purified lymphoid populations. Our results indicate that the hormone binds well to monocytes and natural killer (NK) cells and marginally to purified tonsillar T and B lymphocytes. There was a significant increase in the binding of TSH to purified B cells that were activated in vitro with Staphylococcus aureaus Cowan. In contrast, the binding of TSH to T cells was unaltered when they were stimulated with phytohemagglutinin (PHA). While TSH increases DNA synthesis and intracellular cAMP levels of FRTL-5 rat thyroid cells, it did not have such stimulatory effects on lymphocytes. However, there was a moderate increase in Ig production by activated B lymphocytes when they were cultured in the presence of the hormone. A possible function for TSH as a link between the immune system and the thyroid is discussed.

Immunorestoration in children with recurrent respiratory infections treated with isoprinosine.

Wiedermann D, Wiedermannova D, Lokaj J
Department of Pathological Physiology, Medical Faculty, J.E. Purkyne University, Brno, Czechoslovakia.
Int J Immunopharmacol 1987;9(8):947-9

In 27 children, 4-8 years old, with recurrent respiratory infections of the upper and lower respiratory tracts Isoprinosine (ISO) tablets were administered for 7-10 days at daily doses of 50-100 mg/kg. Clinical signs of acute respiratory disease, including temperature abnormalities and subjective complaints, subsided in a short time and the children showed no symptoms for periods ranging from several weeks to several months following the therapy. The children were selected for immunotherapy with ISO on the basis of their low levels of E-rosette forming cells in peripheral blood. Several immune function parameters assessed immediately after treatment with ISO and compared with those obtained before illness and ISO administration. Low levels of T-lymphocytes returned to normal after ISO therapy, B-lymphocyte relative and absolute numbers, however, were not affected by the treatment. Nor were any changes due to ISO found in immunoglobulins, complement components, beta 2-microglobulin and C-reactive protein. Moreover, ISO had no stimulative effect on spontaneous tetrazolium reductase activity of granulocytes but it showed a slight inhibition of their phagocytosis-associated metabolic activity.

Isoprinosine abolishes the blocking factor-mediated inhibition of lymphocyte responses to Epstein-Barr virus antigens and phytohemagglutinin.

Sundar SK; Menezes J
Int J Immunopharmacol 1986;8(1):101-6

Acute infectious mononucleosis (IM) is accompanied by measurable abnormalities of immune function, including a transient immunosuppression. The sera of patients with acute IM contain an IgG blocking factor which binds to T-lymphocytes and decreases their responses to antigens and mitogens. The experiments reported herein indicate that isoprinosine, an immunopotentiating agent, can reverse this inhibition of T cells by IM-associated IgG blocking factor. Isoprinosine may be a useful tool in understanding the interactions between blocking factors and lymphocytes; moreover, isoprinosine may be of value in patients with abnormal clinical responses to Epstein-Barr virus (EBV) such as chronic IM or persistent active EBV infections.

Isoprinosine as an immunopotentiator in an animal model of human osteosarcoma.

Tsang KY; Fudenberg HH
Int J Immunopharmacol 1981;3(4):383-9

The effects of isoprinosine (ISO) on the immune responses (Con A-induced lymphocyte proliferation, monocyte chemotactic responsiveness, and "natural killer" cytotoxicity) of normal hamsters and hamsters with human osteosarcoma (OS) were investigated. Human osteosarcoma was induced in newborn inbred hamsters (LHX/SsLAK) after induction of tolerance in utero. In vitro, ISO increased Con A-induced proliferation of peripheral blood lymphocytes (PBL) from normal hamsters by 23.4-48.9% and from OS-bearing hamsters by 58.1-107.4% over controls (Con A alone). When ISO was administered in vivo by intraperitoneal injection. Con A-induced proliferation of PBL from both normal and OS-bearing recipients in vitro was increased by 50-55% at 1, 3 and 5 days after injection. The chemotactic responsiveness of monocytes from OS-bearing hamsters was also significantly increased (59.1-97.4%) at 1, 3 and 5 days after injection of ISO. Natural killer cytotoxicity was augmented at 1, 3 and 5 days after injection of ISO by 31.7-83.6% in normal hamsters and 54.6-184% in OS-bearing hamsters. These results indicate that ISO can produce a generalized enhancement of immune function in hamsters with OS.

The effect of Biostim (RU-41740) onthe expression of cytokine mRNAs in murine peritoneal macrophages in vitro.

Meredith C, Scott MP, Pekelharing H, Miller K
Immunotoxicology Department, British Industrial Biological Research Association, Carshalton, Surrey, U.K.
Toxicol Lett 1990 Oct;53(3):327-37

The immunomodulatory agent Biostim (RU-41740) was investigated for its ability to induce the expression of cytokine mRNAs in murine peritoneal macrophages in vitro. Northern blot analysis showed that in quiescent macrophage populations, both IL-1 alpha and IL-1 beta mRNA levels were dramatically increased in response to 1 microgram/ml Biostim. Dot-blot analysis showed that in quiescent macrophage populations the expression of mRNAs for IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha could be elevated by concentrations of Biostim as low as 1-10 pg/ml, detectable after 3 h exposure. In parallel experiments LPS was effective only at the higher concentration of 10 ng/ml. Time-course analysis showed that the expression of these cytokine mRNAs was transient, peaking after 1-3 h; only transcripts of IL-1 beta were detectable after 23 h exposure. No effects were seen on the expression of actin, a high-turnover housekeeping gene. We propose that this type of analysis represents a sensitive, specific and reproducible method for assessing the ability of drugs and chemicals to modulate the expression of cytokines that play a pivotal role in the induction of the immune response.

Isoprinosine (inosine pranobex BAN, INPX) in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.

Glasky AJ; Gordon JF
Cancer Detect Prev Suppl 1987;1:597-609

The immunopharmacologic effects of Isoprinosine (INPX) have been associated with clinical benefit to the patient in a number of conditions characterized by immunodeficiency of diverse etiology. Immunodepressed homosexuals at risk of developing acquired immunodeficiency syndrome (AIDS) treated with placebo or INPX experienced an increase in the function and number of immunocompetent cells associated with clinical improvement. A multicenter trial designed to confirm these results has demonstrated that INPX produced an increase in natural killer (NK)-cell activity, total T cells, and T-helper cells, with certain effects persisting for months after completion of the 28-day treatment period. INPX-treated patients also experienced clinical improvement and decreased incidence of progression to AIDS. The administration of INPX for longer periods to patients with frank AIDS under a compassionate-use protocol has also proved useful. Clinical benefit associated with INPX treatment has been demonstrated in other patients with a depressed immune response, such as aged patients, cancer patients, severely burned patients, ill patients, and surgery patients. This program of clinical trials supports the therapeutic use of INPX in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.

Immunological effests of Isoprinosine as a pulse immunotherapy in melanoma and ARC patients in melanoma and ARC patients

Pompidou A; Soubrane C; Cour V; Telvi L; Meunier C; Jacquillat C
Cancer Detect Prev Suppl; 1:457-62 1987

Immunomodulatory effect of Isoprinosine are presented in melanoma and HTLV-III/LAV infected patients. Isoprinosine (50 mg/kg) was used as a pulse immunotherapy according to two different schedules: A) 5 days every 15 days and B) 5 days every 15 days for 2 months, then 5 days every 2 months. The patients' immunological profiles were tested before and during the treatment in terms of T-cell subsets, cell number requirement for PHA-induced proliferation, and delayed hypersensitivity reaction to recall antigens. Primary malignant melanoma patients are randomized between surgery alone or associated to isotherapy (schedule A or B). Schedule A,after an initial improvement of surgery-induced immune deficiency, is responsible for an immunodepression, whereas schedule B determines a prolonged restoration in immune responses in melanoma and AIDS related complex or Kaposi sarcoma patients as well. In vitro effects of Isoprinosine on HTLV-III/LAV infection are presented. These data exhibit 1) the need of an immunological follow-up during isotherapy and 2) the immunological benefit of a pulse immunotherapy during acquired immunodeficiencies related to cancer surgery or to HTLV-III/LAV infection in man.

A modified determination of coenzyme Q10 in human blood and CoQ10 blood levels in diverse patients with allergies.

Ye CQ, Folkers K, Tamagawa H, Pfeiffer C
Institute for Biomedical Research, University of Texas, Austin.
Biofactors 1988 Dec;1(4):303-6

Two situations required a modified determination of coenzyme Q10 (CoQ10) in human blood and organ tissue. Blood from patients with AIDS and cancer raised apprehensions about safety to an analyst, and the number of specimens for analysis is increasing enormously. A modified determination replaces silica gel-TLC with disposable Florisil columns, and steps were simplified to allow more analyses per unit time. Data from the modified determination are quantitatively compatible with data from older and tedious procedures. This determination was used for blood from 36 diverse patients with allergies. The mean CoQ10 blood level of these patients is not different from the mean level of so-called normal individuals, but approximately 40% (14/36) of these allergic patients had levels up to 0.65 micrograms/ml, which is the level of dying class IV cardiac patients. The biosynthesis of CoQ10 in human tissues is a complex process that requires several vitamins and micronutrients, so that countless vitamin-unsupplemented Americans may be deficient in CoQ10. The relationship of allergies to autoimmune mechanisms and immunity, and the established relationship of CoQ10 to immune states, may be a rationale for therapeutic trials of administering CoQ10 to patients with allergies who have low CoQ10 blood levels and are very likely deficient.

Carnitine in human immunodeficiency virus type 1 infection/acquired immune deficiency syndrome.

Mintz M
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School at Camden 08103, USA.
J Child Neurol 1995 Nov;10 Suppl 2:S40-4

There is an increasing body of evidence that subgroups of patients infected with human immunodeficiency virus type 1 possess carnitine deficiency. Secondary carnitine deficiencies in these individuals may result from nutritional deficiencies, gastrointestinal disturbances, renal losses, or shifts in metabolic pathways. However, tissue depletion precipitated by drug toxicities, particularly zidovudine, is a major etiology and concern. Carnitine deficiency may impact on energy and lipid metabolism, causing mitochondrial and immune dysfunction. There are convincing laboratory data showing the in vitro ameliorative effects of L-carnitine supplementation of zidovudine-induced myopathies and lymphocyte function. Studies measuring the impact of L-carnitine supplementation on clinical characteristics are ongoing.

Oxidative damage and mitochondrial decay in aging.

Shigenaga MK, Hagen TM, Ames BN
Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720
Proc Natl Acad Sci U S A 1994 Nov 8;91(23):10771-8

We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine.

De Simone C; Famularo G; Tzantzoglou S; Trinchieri V; Moretti S; Sorice F
AIDS (United States) May 1994, 8 (5) p655-60

OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4-N-trimethyl-am monio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine.

DESIGN: Immunopharmacologic study.

METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation.

RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels.

CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.

Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances.

Franceschi C, Cossarizza A, Troiano L, Salati R, Monti D
Institute of General Pathology, University of Modena, Italy.
Int J Clin Pharmacol Res 1990;10(1-2):53-7

Several immune parameters--particularly T-cell dependent immune responses--are altered in aged subjects. To test the hypothesis that they may be the consequence of more general age-related lymphocyte biochemical alterations, and particularly of the energy producing system, the effect of L-carnitine and acetyl-L-carnitine on cell proliferation was studied in peripheral blood lymphocytes from donors of different ages. The results showed that phytohaemagglutinin-induced peripheral blood lymphocyte proliferation was markedly increased in L-carnitine- or acetyl-L-carnitine-preloaded lymphocytes from young and especially from old subjects. Cells from aged subjects considerably improved their defective proliferative capability. Preliminary observations suggest that L-carnitine-preloading also protected peripheral blood lymphocytes from old donors when such cells were exposed to an oxidative stress.