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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 two PTK 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.
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.
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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