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Immune Enhancement



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.)


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.

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.

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.

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.

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.

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.

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.

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.

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.

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