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13
Vitamin E, Vitamin C, and Immune Response: Recent Advances

Laura C. Rall

Simin Nikbin Meydani1

Introduction

Tocopherols (the major group of compounds with vitamin E biological activity) are known chemically as antioxidants; they prevent propagation of the oxidation of unsaturated fatty acids by trapping peroxyl free radicals (NRC, 1989). Vitamin E is found in cellular membranes of animal tissues, associated with polyunsaturated fatty acids in phospholipids. Here, vitamin E serves as the primary defense against potentially harmful oxidation reactions (NRC, 1989).

In addition to vitamin E, ascorbic acid (vitamin C) is one of the other essential nutrients, assisting in this antioxidant defense system by protecting against lipid peroxidation (Frei et al., 1988). In fact, vitamin C has been shown to function by sparing or reconstituting vitamin E, thus protecting lipid membranes (Packer et al., 1979). Although it is widely believed that the basic role of vitamin E is its function as an antioxidant (NRC, 1989), vitamin C has other important functions in numerous biological systems, including the synthesis of hormones, neurotransmitters, collagen and carnitine; the

1  

Simin Nikbin Meydani, Nutritional Immunology Laboratory, U.S. Department of Agriculture-Human Nutrition Research Center on Aging at Tufts, Boston, MA 02111



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--> 13 Vitamin E, Vitamin C, and Immune Response: Recent Advances Laura C. Rall Simin Nikbin Meydani1 Introduction Tocopherols (the major group of compounds with vitamin E biological activity) are known chemically as antioxidants; they prevent propagation of the oxidation of unsaturated fatty acids by trapping peroxyl free radicals (NRC, 1989). Vitamin E is found in cellular membranes of animal tissues, associated with polyunsaturated fatty acids in phospholipids. Here, vitamin E serves as the primary defense against potentially harmful oxidation reactions (NRC, 1989). In addition to vitamin E, ascorbic acid (vitamin C) is one of the other essential nutrients, assisting in this antioxidant defense system by protecting against lipid peroxidation (Frei et al., 1988). In fact, vitamin C has been shown to function by sparing or reconstituting vitamin E, thus protecting lipid membranes (Packer et al., 1979). Although it is widely believed that the basic role of vitamin E is its function as an antioxidant (NRC, 1989), vitamin C has other important functions in numerous biological systems, including the synthesis of hormones, neurotransmitters, collagen and carnitine; the 1   Simin Nikbin Meydani, Nutritional Immunology Laboratory, U.S. Department of Agriculture-Human Nutrition Research Center on Aging at Tufts, Boston, MA 02111

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--> detoxification of exogenous compounds; and cytochrome P-450 activity (reviewed in NRC, 1989). However, recent evidence has also shown that vitamins E and C are needed for normal function of the immune system (Anderson et al., 1980) (reviewed in M. Meydani, 1995). The present Recommended Dietary Allowance (RDA) for vitamin E is 10 mg of α-tocopherol equivalents (TE)/d for male adults and 8 mg/d for women; for vitamin C the RDA is 60 mg/d for adults regardless of gender (NRC, 1989). The recommendation for vitamin E is based on customary dietary intakes from U.S. food sources, while in the case of vitamin C, the RDA represents a balance between the amount necessary to prevent overt symptoms of deficiency and the amount beyond which the nutrient is not retained by the body (NRC, 1989). In both instances, the recommendation is admittedly somewhat arbitrary (NRC, 1989), and in neither case was the RDA designed with the aim of promoting optimal health benefits. Although vitamins E and C have long been recognized for their antioxidant properties, increasing attention has been focused on their abilities, along with those of other antioxidants, to reduce the risk of chronic disease. The question of an optimal level of intake for health promotion and chronic disease prevention is beyond the scope of this chapter. Instead, this review will focus on the effects of vitamins E and C on immunity and the implications of vitamin status and supplementation for various populations and disease states. Specifically, the effects of these nutrients during aging, acquired immunodeficiency disease (AIDS), coronary heart disease (CHD), cancer, allergy, and exercise will be considered. Aging Most evidence indicates a progressive decline in immune response in both laboratory animals and human subjects with advancing age. Those parameters that seem to decrease with age include thymic tissue mass, antibody response, delayed-type hypersensitivity (DTH) response, T-cell proliferative response to mitogen stimulation, and the proportion of T-cell subsets with naive cell surface markers (Makinodan, 1995). However, other immune parameters frequently increase with age, including variability in immune responses among individuals, production of autoantibodies, production of monoclonal immunoglobulins, and the proportion of T-cell subsets with memory membrane markers (Makinodan, 1995). The net result of these changes is a dysregulated immune response accompanied by increased morbidity and mortality among the elderly (reviewed in Goodwin, 1995). Research efforts are now directed at finding ways to alleviate this dysregulation of immunity and, ultimately, to reduce the age-associated increase in morbidity and mortality. Interestingly, most of the nutritional interventions that are successful in improving immunologic vigor in aging humans are antioxidant in nature (S.N. Meydani et al., 1995).

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--> Vitamin E A series of controlled clinical trials by S.N. Meydani et al. (1990, 1997a) and M. Meydani et al. (1994) have demonstrated that vitamin E supplementation of elderly persons may enhance the immune response. In the first study (S.N. Meydani et al., 1990), healthy elderly men (> 60 years old) were supplemented with 800 mg 2-ambo-α-tocopherol or placebo/d for 30 days. Their diets provided adequate amounts of vitamin E and other nutrients. All subjects resided and consumed all of their food in the Metabolic Research Unit at the Jean Mayer U.S. Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University. Before and after supplementation, blood samples were collected for measurement of various biochemical and immunologic indexes, and DTH was measured as an in vivo indicator of cell-mediated immunity (CMI). Results showed that vitamin E supplementation was associated with increased plasma vitamin E, DTH score, mitogenic response to concanavalin A (Con-A), and interleukin (IL)-2 production. Vitamin E supplementation was also associated with decreased prostaglandin (PG)E2 production by peripheral blood mononuclear cells (PBMCs) and decreased plasma lipid peroxide concentrations. Although this study did demonstrate a beneficial effect of vitamin E on immune response, the study was of relatively short duration, using a high dosage of vitamin E. Therefore, to further investigate the effect of long-term supplementation and optimal concentration of vitamin E on the immune response of elderly individuals, a double-blind, placebo-controlled study with 80 free-living, healthy, elderly persons (> 65 years of age) wa was conducted (S.N. Meydani et al., 1997a). Subjects were randomly assigned to receive either placebo, 60, 200, or 800 mg vitamin E/d. Fasting blood samples were collected before and after 1 and 4.5 months of supplementation, and mitogenic response cytokine production, lymphocyte subpopulations, and biochemical indexes were measured. In addition, DTH and antibody response to vaccination were also measured as in vivo indices of immune response. Subjects' health status, weight, dietary intake, and physical activity were monitored for the duration of the study. All three vitamin E-supplemented subject groups demonstrated a significant increase in plasma vitamin E levels and DTH response, while the placebo group showed no increase in plasma vitamin E levels, mitogenic response, or DTH. An additional study was also performed to assess further the effect of long-term vitamin E supplementation on immune response of young versus elderly subjects (M. Meydani et al. 1994). Sixty healthy young and elderly men and women were supplemented with either 400 mg RRR -α-tocopherol or placebo for 6 months. Fasting blood samples were collected before and after 2, 4, and 6 months of supplementation. Levels of plasma α-tocopherol increased among subjects in both age groups after 2 months of supplementation and remained

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--> elevated for the duration of the study. Furthermore, vitamin E reduced levels of plasma lipid peroxides among subjects in all age groups after 2 months of supplementation, but by 6 months, this effect was only observed among the elderly subjects. Vitamin E supplementation also resulted in an increased DTH response in both age groups, although the effect was stronger in elderly compared with young individuals. The findings of this series of clinical trials suggest that vitamin E supplementation of elderly individuals leads to enhancement of in vivo and in vitro measures of immune response. Furthermore, supplementation with large amounts of vitamin E (800 mg) has not been found to have adverse health effects among healthy elderly individuals (S.N. Meydani et al., 1997b). Additional research is currently being conducted to determine the mechanism of the immunoenhancing effect of vitamin E. Vitamin C Compared with vitamin E, there have been fewer studies specifically examining the effects of vitamin C on immune response, particularly among elderly individuals. One study utilized a combination of vitamin A, C, and E supplements among 30 elderly long-stay patients (Penn et al., 1991). Nutritional status and cell-mediated immune function were assessed before and after 28 days of supplementation. CMI was enhanced in the supplemented but not the placebo group, as indicated by an increase in the absolute number of T-cells, T4 subsets, the T4:T8 ratio, and the proliferation of lymphocytes in response to phytohemagglutinin (PHA). The findings of this study suggest that supplementation with antioxidant nutrients can improve cell-mediated immune parameters among elderly long-stay patients; however, the study design prevents the independent effects of each of the nutrients from being determined. Studies that have looked exclusively at vitamin C in terms of its effect on immunocompetence have had inconsistent results. A depletion-repletion study designed to determine the dietary ascorbate requirement to optimize the functions of the vitamin other than prevention of scurvy was carried out in healthy, young-to-middle-aged men (25–43 years of age) (Jacob et al., 1991). Immune and oxidant defense parameters were measured while subjects consumed 5 to 250 mg/d of ascorbic acid over 92 days while residing in a metabolic unit. No changes in proliferation of PBMCs or erythrocyte antioxidant enzymes were observed during depletion or repletion. In contrast, DTH response did decrease during ascorbic acid deficiency; however, repletion for 21 days at 60 or 250 mg ascorbic acid did not restore the mean DTH score to predepletion levels. Therefore, there were no clear differences in the immune and oxidative damage parameters among healthy, young-to-middle-aged men during this depletion-repletion study. Unlike these findings of Jacob et al. (1991), others have found that vitamin C may improve selected immune responses in elderly individuals. For example,

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--> vitamin C supplementation (500 mg daily, given intramuscularly, for 1 month) enhanced lymphocyte proliferative response in vitro and skin reactivity to tuberculin antigen in vivo among elderly individuals with low blood vitamin C levels (Kennes et al., 1983). In addition, increased vitamin C intake (1–3 g/d for 1 week) has been shown by others to stimulate lymphocyte proliferative response (Anderson et al., 1980). Inconsistent findings among studies may be explained by one or more of the following factors: the population studied (young versus elderly), the dosage of vitamin C (pharmacologic levels versus physiologic levels), and the duration of supplementation. Additional studies to examine the effects of vitamin C on immune response, taking into account these various factors, are required before any definitive conclusions can be drawn. Cancer Some experimental and epidemiologic studies have suggested that both vitamins E and C may reduce the risk of various types of cancer. However, the evidence remains controversial either because of the nutrient source (diet or supplement) or the cancer site studied. Both nutrients, via their antioxidant function, may eliminate free radicals and decrease DNA damage by reducing mutagenesis and cell transformation (Block, 1992; M. Meydani, 1995). In addition to its role as an antioxidant, vitamin E may also directly affect various cells of the immune system (i.e., natural killer [NK] and inflammatory cells), leading to an enhanced ability to inhibit tumor production (M. Meydani, 1995). Byers and Guerrero (1995) have recently reviewed all epidemiologic studies on the topic of diet and cancer prevention in which intakes of vitamins E and C or fruit and vegetable consumption were estimated. Results showed that diets high in fruits and vegetables (> 5 servings/d) and, therefore, high in vitamin C are associated with lower risk of cancer of the oral cavity, esophagus, stomach, colon, and lung. The hormone-associated cancers of the breast and prostate appear to be less related to fruit and vegetable intake. Diets high in added vegetable oils, presumably high in vitamin E, have been less consistently associated with reduced cancer risk. However, when studies of vitamins E and C consumed as supplements are considered, there is little support for a protective role of either nutrient against cancer. Therefore, if vitamins E or C are protective against cancer, this effect may be due to their consumption in whole foods, where they are combined with other nutrients or bioactive compounds that together provide a protective effect against cancer. The most prudent approach seems to be one of increasing fruit and vegetable consumption in the diet, thus maximizing the potential benefits of antioxidant nutrients in terms of cancer prevention.

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--> Aids Considerable evidence has accumulated that HIV-infected patients are under chronic oxidative stress as evidenced by increased levels of hydroperoxides and malondialdehyde (MDA) in serum (Pace and Leaf, 1995). This oxidative stress may contribute to various aspects of immune dysfunction in HIV disease pathogenesis, including viral replication, inflammation, decreased immune cell proliferation, loss of immune function, and apoptosis (Pace and Leaf, 1995). Furthermore, changes in levels of antioxidant nutrients have also been observed in various tissues of these patients (Pace and Leaf, 1995). Therefore, vitamins E, C, and other antioxidants may have immunoenhancing properties that could help normalize immune dysfunctions that lead to full-blown AIDS (Wang and Watson, 1993). A number of studies by Watson and colleagues illustrate this point with regard to vitamin E (Wang et al., 1994a,b, 1995). These researchers have used C57BL/6 mice infected with LP-BM5 retrovirus to cause murine AIDS, which is functionally similar to human AIDS. Animals were supplemented with at least a 15-fold increase of vitamin E in a liquid diet (160 IU/liter). Vitamin E supplementation led to increased NK cell cytotoxicity, splenocyte proliferation, and IL-2 and interferon-γ levels, all of which are suppressed by retrovirus infection. Vitamin E also led to decreased IL-6, IL-10, and tumor necrosis factor [TNF]-α production, all of which had been increased by retrovirus infection. These findings suggest that high levels of vitamin E supplementation can modulate cytokine production and normalize immune dysfunctions during the development of murine AIDS. It is not clear, however, whether these immunological changes alter the clinical outcome of the disease. Human studies have also suggested that vitamin E is involved in HIV pathogenesis, perhaps via its effect on IgE production (Shor-Posner et al., 1995). Elevated production of IgE has been demonstrated in persons infected with HIV-1 (Israel-Biet et al., 1992) and is associated with T-cell dysregulation, opportunistic infections, and an increase in allergic reactions (Carr et al., 1991; Gruchalla and Sullivan, 1991; Pedersen et al., 1991; Schwartzman et al., 1991; Wolf et al., 1991; Wright et al., 1990). Furthermore, IgE production has been shown to be affected by vitamin E status in an animal model (Inagaki et al., 1984). In a study of 100 asymptomatic HIV-1 seropositive and 42 HIV-1 seronegative homosexual men, Shor-Posner et al. (1995) found that the HIV-1 seropositive subjects with biochemical evidence of vitamin E deficiency had elevated IgE levels (independent of CD4 counts) compared with the seronegative controls and tended to have higher levels than the vitamin E-adequate seropositive subjects. In addition, subjects with low plasma vitamin E levels also had low dietary intakes of vitamin E compared with nondeficient HIV-seropositive subjects. Therefore, nutritional status seems to be an important factor in the IgE elevation observed during the early stages of HIV-1 disease, and supplementation may be warranted in HIV-1-infected individuals with

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--> vitamin E deficiency. Indeed, a study of HIV-infected patients has shown that, among HIV-seropositive individuals, the consumption of vitamins E and C in the form of supplements is in the megadose range (mean intake of 239 and 905 mg/d, respectively), driven in part by information received from health professionals and the media regarding the possible benefits of increased intakes of these nutrients (Martin et al., 1991). In the Multicenter AIDS Cohort Study of 281 HIV-1 seropositive homosexual or bisexual men, it has been shown that individuals with the highest level of total intake of vitamin C from food and supplements had a significantly decreased rate of progression to AIDS (Tang et al., 1993). In a multinutrient statistical model, however, vitamin C remained only marginally significant, which suggests that when taken in combination with other nutrients, vitamin C may have less of an effect compared to the benefits of other nutrients. Although AIDS is ultimately a fatal disease, improved means of treating infections can greatly prolong survival (Gorbach et al., 1993). Supplements of vitamins and minerals, including vitamins E and C, to combat increased oxidative stress are a recommended part of dietary interventions for AIDS patients (Gorbach et al., 1993). However, appropriate dosages have not yet been determined. Asthma and Lung Function It is possible that antioxidant defenses are of particular importance in the lung since a naturally high exposure to oxygen may be further increased by oxidative processes during inflammation and inhalation of oxidant air pollutants (Burney, 1995). Such damage could lead to permanent loss of lung function over time. It has, therefore, been hypothesized that vitamins E and C, acting either as antioxidants or through a direct effect on immune function, may reduce airway inflammation, thereby decreasing the severity of asthma or even preventing its occurrence in susceptible individuals (Hatch, 1995; Troisi et al., 1995). Associations between several dietary factors assessed by a semiquantitative food frequency questionnaire and the incidence of asthma over a 10-y period were evaluated as part of the Nurses' Health Study of 77,866 women 34 to 68 years of age (Troisi et al., 1995). Women in the highest quintile of vitamin E intake from diet alone had a reduced risk of asthma (relative risk 0.53, p = 0.0005) compared with women in the lowest quintile of dietary intake. However, the use of vitamin C or E supplements was associated with a significant increase in the risk of asthma, although this seemed to be due to women at high risk of asthma initiating the use of vitamin supplements prior to diagnosis. These data suggest that although antioxidant supplementation is not an important determinant of adult-onset asthma, dietary intake of vitamin E may have a modest protective effect.

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--> In another epidemiologic study, stronger evidence is provided that vitamin C and possibly vitamin E may influence lung function in middle and later life (Britton et al., 1995). In a cross-sectional survey of 2,633 subjects 18 to 70 years of age living in England, researchers found that higher dietary intakes of both vitamins C and E were associated with improved lung function (measured by spirometry). However, these two nutrients were significantly correlated, and after adjustment, there was no independent effect of vitamin E on lung function after allowing for the effect of vitamin C. These findings are supported by results from NHANES I, which have also suggested that dietary vitamin C intake has a protective effect on pulmonary function (Schwartz and Weiss, 1994). Although these studies must be interpreted with caution, they do suggest that dietary intake of foods rich in vitamins C and E may be beneficial in decreasing the risk of asthma or reduced lung function, particularly among individuals at increased risk for these conditions (for example, smokers). Exercise Evidence exists that lipid peroxidation products suggestive of oxidative stress increase after exercise (Davies et al., 1982), although this has not been consistently observed, even after an acute bout of exercise (Cannon et al., 1990). Whether or not oxidative damage occurs during exercise seems to depend on a number of factors, including the intensity of exercise, the location of the sampling site, and the state of training of the subjects (Witt et al., 1992). Intense or exhaustive exercise in untrained individuals is more likely to result in oxidative damage, which is more likely to be detected in muscle samples than blood (Witt et al., 1992). Furthermore, if oxidative stress is great enough to overcome antioxidant defense systems in the body, then oxidative damage will inevitably occur (Witt et al., 1992). Therefore, a great deal of attention has recently been focused on whether antioxidant nutrients, in particular vitamins E and C, may help to reduce oxidative stress and damage during exercise. Most studies do demonstrate a benefit of vitamins E and C in reducing measures of oxidative stress following exercise. Levels of breath pentane and serum MDA, indirect measures of free radical generation, have been shown to be lower at rest and after an acute bout of exercise among young healthy men consuming 1,000 mg vitamin C and 592 mg α-tocopherol equivalents per day compared with subjects receiving a placebo (Kanter et al., 1993). In addition, both nutrients individually have also been shown to have beneficial effects in terms of reducing exercise-induced oxidative injury. M. Meydani et al. (1993) have demonstrated that vitamin E (800 IU dl-α-tocopherol) taken daily for 48 days by a group of young (22–29 years) and older (55–74 years) men led to lower urinary thiobarbituric acid excretion after a bout

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--> of eccentric exercise,2 suggesting that vitamin E provides protection against exercise-induced oxidative injury. Furthermore, in a double-blind, placebo-controlled study, when 21 male subjects took vitamin E supplements (800 IU/d) for 48 days and then ran downhill on an inclined treadmill (Cannon et al., 1991), endotoxin-induced secretion of IL-1β was increased 154 percent in cells obtained from placebo subjects 24 hours postexercise; however, no significant exercise-related changes were observed in cells from vitamin E-supplemented subjects. This IL-1β response to vitamin E supplementation is consistent with a mechanism involving oxygen radicals. Specifically, exercise-induced oxygen radicals increased IL-1β secretion after an acute bout of eccentric exercise in cells from subjects taking a placebo but not from subjects taking vitamin E. In addition, urinary 3-methylhistidine, a measure of muscle proteolysis, was associated with IL-1β production. These findings suggest that vitamin E may be beneficial in reducing the oxygen radical-induced muscle damage of eccentric exercise. In support of these findings, others have also shown that vitamin E supplementation reduces expired pentane and MDA levels in response to exercise (Dillard et al., 1978; Sumida et al., 1989). In addition, vitamin C supplementation (600 mg/d) has also been shown to reduce the incidence of upper respiratory tract infections in ultramarathon runners compared with subjects taking a placebo (Peters et al., 1993). In summary, there is considerable evidence regarding the benefits of vitamin E and C supplementation in terms of reducing oxidative stress and/or damage during exercise. However, data remain incomplete, particularly in terms of the optimal amount of supplementation that should be recommended to achieve these benefits. Authors' Conclusions By virtue of their role as antioxidant and immuno-enhancing nutrients, the benefits of vitamins E and C have been increasingly recognized and applied to various clinical situations including aging, cancer, AIDS, asthma, and exercise. The ultimate impact of these nutrients has been variable however, due to differences in whether dietary or supplemental sources of the vitamin are considered, and if supplements are utilized, the dosage and whether combinations of antioxidants are administered. Most studies show that vitamin E can improve the immune response during aging and suggest that it can reduce the oxidative damage that may contribute to cancer, to the complications of AIDS, and to asthma as well as the damage that may occur during exercise. The strongest evidence seems to be associated with higher dietary intakes of vitamin E, as opposed to consumption of vitamin E in 2   Eccentric exercise is when external resistance exceeds muscle force, the muscle lengthens and develops tension.

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--> the form of supplements. The exceptions seem to be in the case of exercise and aging, for which supplementation with high levels of vitamin E have been utilized in order to achieve beneficial effects. In terms of vitamin C, the evidence seems less conclusive for a benefit of this nutrient during aging, although as with vitamin E, a reduction in oxidative stress has been observed as a result of high dietary intake (or supplementation in the case of exercise) of vitamin C in cancer, AIDS, and asthma patients and with exercise. Additional research is necessary in order to further define the possible benefits of vitamins E and C in various disease states as well as their optimal dosages. Further investigation is also warranted to elucidate more fully the antioxidant and immuno-enhancing properties of these nutrients. Acknowledgments This project has been funded at least in part with federal funds from the U.S. Department of Agriculture, Agricultural Research Service, under contract number 53-K06-01. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. The authors would like to thank Timothy S. McElreavy for preparation of this manuscript. References Anderson, R., R. Oosthuizen, R. Maritz, A. Heron, and A. J. VanRensburg. 1980. The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune function in volunteers. Am. J. Clin. Nutr. 33:71-76. Block, G. 1992. Vitamin C status and cancer: Epidemiologic evidence of reduced risk. Ann. N.Y. Acad. Sci. 669:280-292. Britton, J.R., I.D. Pavord, K.A. Richards, A.J. Knox, A.F. Wisniewski, S.A. Lewis, A.E. Tattersfield, and S.T. Weiss. 1995. Dietary antioxidant vitamin intake and lung function in the general population. Am. J. Respir. Crit. Care Med. 151:1383-1387. Burney, P. 1995. The origins of obstructive airways disease: A role for diet? Am. J. Respir. Crit. Care Med. 151:1292-1293. Byers, T., and N. Guerrero. 1995. Epidemiologic evidence for vitamin C and vitamin E in cancer prevention. Am. J. Clin. Nutr. 62:1385S-1392S. Cannon, J.G., S.N. Meydani, R.A. Fielding, M.A. Fiatarone, M. Meydani, M. Farhangmehr, S.F. Orencole, J.B. Blumberg, and W.J. Evans. 1991. Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis. Am. J. Physiol. 260:R1235-R1240. Cannon, J.G., S.F. Orencole, R.A. Fielding, M. Meydani, S.N. Meydani, M.A. Fiatarone, J.B. Blumberg, and W.J. Evans. 1990. Acute phase response in exercise: Interaction of age and vitamin E on neutrophils and muscle enzyme release. Am. J. Physiol. 259:R1214-R1219.

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--> Carr, A., D.A. Cooper, and R. Penny. 1991. Allergic manifestations of human immunodeficiency (HIV) infection. J. Clin. Immunol. 11:55-64. Davies, K.J.A., L. Packer, and G.A. Brooks. 1982. Free radicals and tissue damage produced by exercise. Biochem. Biophys. Res. Commun. 107:1198-1205. Dillard, C.J., R.E. Litov, W.M. Savin, E.E. Dumelin, and A.L. Tappel. 1978. Effects of exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J. Appl. Physiol. 45:927-932. Frei, B., R. Stocker, and B.N. Ames. 1988. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc. Natl. Acad. Sci. USA 85:9748-9752. Goodwin, J.S. 1995. Decreased immunity and increased morbidity in the elderly. Nutr. Rev. 53:S41-S46. Gorbach, S.L., T.A. Knox, and R. Roubenoff. 1993. Interactions between nutrition and infection with human immunodeficiency virus. Nutr. Rev. 51:226-234. Gruchalla, R.S., and T.J. Sullivan. 1991. Detection of human IgE to sulfamethoxazole by skin testing with sulfamethoxazoyl-poly-l-tyrosine. J. Allergy Clin. Immunol. 88:784-792. Hatch, G.E. 1995. Asthma, inhaled oxidant, and dietary antioxidants. Am. J. Clin. Nutr. 61:625S-630S. Inagaki, N., H. Nagai, and A. Koda. 1984. Effect of vitamin E on IgE antibody formation in mice. J. Pharmacobiodynamics 7:70-74. Israel-Biet, D., F. Labrousse, J.M. Tourani, H. Sors, J.M. Andrieu, and P. Even. 1992. Elevation of IgE in HIV-infected subjects: A marker of poor prognosis. J. Allergy Clin. Immunol. 89:68-75. Jacob, R.A., D.S. Kelley, F.S. Pianalto, M.E. Swendseid, S.M. Henning, J.Z. Zhang, B.N. Ames, C.G. Fraga, and J.H. Peters. 1991. Immunocompetence and oxidant defense during ascorbate depletion of healthy men. Am. J. Clin. Nutr. 54:1302S-1309S. Kanter, M.M., L.A. Nolte, and J.O. Holloszy. 1993. Effects of an antioxidant vitamin mixture on lipid peroxidation at rest and postexercise. J. Appl. Physiol. 74:965-969. Kennes, B., I. Dumont, D. Brohee, C. Hubert, and P. Neve. 1983. Effect of vitamin C supplements on cell-mediated immunity in old people. Gerontology 29:305-310. Makinodan, T. 1995. Patterns of age-related immunologic changes. Nutr. Rev. 53:S27-S34. Martin, J.B., T. Easley-Shaw, and C. Collins. 1991. Use of selected vitamin and mineral supplements among individuals infected with human immunodeficiency virus. J. Am. Diet. Assoc. 91:476-478. Meydani, M. 1995. Vitamin E. Lancet 345:170-175. Meydani, M., W.J. Evans, G. Handelman, L. Biddle, R.A. Fielding, S.N. Meydani, J. Burrill, M.A. Fiatarone, J.B. Blumberg, and J.G. Cannon. 1993. Protective effect of vitamin E on exercise-induced oxidative damage in young and older adults. Am. J. Physiol. 264:R992-R998. Meydani, M., S.N. Meydani, L. Leka, J. Gong, and J.B. Blumberg. 1994. Effect of long-term vitamin E supplementation on lipid peroxidation and immune responses of young and old subjects. FASEB J. 8:A415. Meydani, S.N., M. Meydani, J.B. Blumberg, L. Leka, M. Pedrosa, B.D. Stollar, and R. Diamond. 1997b. Safety assessment of long-term vitamin E supplementation in healthy elderly. FASEB J. 10:A448. Meydani, S.N., M.P. Barklund, S. Liu, M. Meydani, R.A. Miller, J.G. Cannon, F.D. Morrow, R. Rocklin, and J.B. Blumberg. 1990. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am. J. Clin. Nutr. 52:557-563. Meydani, S.N., M. Meydani, J.B. Blumberg, L. Leka, M. Pedrosa, B.D. Stollar , and R. Diamond. 1997a. Safety assessment of long-term vitamin E supplementation in healthy elderly. FASEB J. 10:A448. Meydani, S.N., M. Meydani, J.B. Blumberg, L.S. Leka, G. Siber, R. Loszewski, C. Thompson, M.C. Pedrosa, R.D. Diamond, and B.D. Stollar. 1997b. Vitamin E

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--> Wang, Y., D.S. Huang, S. Wood, and R.R. Watson. 1995. Modulation of immune function and cytokine production by various levels of vitamin E supplementation during murine AIDS. Immunopharmacology 29:225-233. Witt, E.H., A.Z. Reznick, C.A. Viguie, P. Starke-Reed, and L. Packer. 1992. Exercise, oxidative damage, and effects of antioxidant manipulation. J. Nutr. 122:766-773. Wolf, R., J. Oph, and I. Yust. 1991. Atopic dermatitis provoked by AL721 in a patient with acquired immunodeficiency syndrome. Ann. Allergy 66:421-422. Wright, D.N., R.P. Nelson, D.K. Ledford, E. Fernandez-Caldas, W.L. Trudeau, and R.F. Lockey. 1990. Serum IgE and human immunodeficiency virus (HIV) infection. J. Allergy Clin. Immunol. 85:445-452. Discussion HARRIS LIEBERMAN: I just wanted to say that I think not only are the methods that you have used in your work of direct relevance to the military population, but the population that you are working with actually has many similarities with regard to the kind of problems that we have. We are talking about studying healthy people who have potentially subclinical deficits in function as opposed to more severe kinds of deficits in function associated with severe illness. I did want to ask you a question, too. You had some sort of informal data on illness levels in the patients in your vitamin E-supplemented study. What was the shape of the dose-response function in those self-reports? Did it appear that the 200 mg was also optimal? SIMIN NIKBIN MEYDANI: It looked like it, but that is just about it. You know, the numbers are very small, and I am even stretching it showing the combined data [all three vitamin E-supplement group vs. placebo], but it looks like that. STEVE GAFFIN: Any possible additional benefits from omega-3 fatty acids? SIMIN NIKBIN MEYDANI: We have done work with the elderly and omega-3 fatty acids. Actually, if you give it to the elderly, it causes a decrease in T-cell proliferation—also in DTH—and we think that is because when you give omega-3 fatty acids, you increase the requirement for vitamin E. Now, if you combine vitamin E with omega-3 fatty acids, you might see a very different picture, but by itself, it actually decreases T-cell function, but it also decreases cytokines—the inflammatory cytokines like IL-1 and TNF, which could be useful.

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--> BRUCE BISTRIAN: This comment really refers to both Dr. Shippee's talk and yours also. I was involved in the early assessment of CMI, the skin test, and I would like to mention to you because of the importance of this that whereas it looks like transformation data have, to my knowledge, never been collated with any clinical outcome, the anergy data have been extraordinarily well collated with many, many different populations, and in that regard if you recategorize, it is very important, the antigen should be very strictly defined, that being less than 2 mm to any of the antigens because if you have people like that, their risk if they were like that for a long period of time, we have known from the elderly, the risk of outcome is dramatically impaired. Most important for the military: if you have true anergy and those soldiers are wounded, they are often in the hospital and would probably be impaired by that. I would be very careful and concerned how much anergy is truly defined, how much you are producing. If you are already producing substantial amounts of anergy, then you have a very serious concern. SIMIN NIKBIN MEYDANI: I think that is a very good point. ERHARD HAUS: Basically that is what I think. First of all, you cannot comment that antioxidants cause decantenation, which in a military environment with sleep deprivation might try to convince them it is all right. Any thoughts about this? SIMIN NIKBIN MEYDANI: I would be able to tell you probably in 3 or 5 months because we are doing a study with that currently. So, I will be able to tell you that. ROBERT NESHEIM: Thank you very much. Because of the time schedule, with the commander coming at lunch, we have to move fast. But go ahead. HARRIS LIEBERMAN: Is arachidonic acid released? SIMIN NIKBIN MEYDANI: That, of course, could be a possibility. The reason we didn't concentrate on it was that as I said we don't see any difference in the level of arachidonic acid in the macrophages, and also if you noticed, there was only an increase in cyclooxygenase and 5-lipoxygenase products and not in the 12 and 15-lipoxygenase products. So, that indicates to me that perhaps it is not the release of arachidonic acid, because if it was release of arachidonic acid and a change in phospholipase activity, it would be likely that all the products of arachidonic acid would be affected. But I think that is a possibility.

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--> DR. KENNEDY: This is a comment more than a question because I am about to go on study for a month, but what did you use to stimulate IL-2? SIMIN NIKBIN MEYDANI: PHA and Con-A. We either used PHA or Con-A, and both of them work. DR. KENNEDY: Ron didn't present all our work. We have some interesting data to suggest that part of the stress response in Special Forces may be due to a shift in the paradigm from Th2 [T-helper 2] to Th1, and also we are interested in some recent data that look at surgical stress. Have you looked at FOS3 or API4? SIMIN NIKBIN MEYDANI: Not yet, but as part of looking at the mechanism, that is something we will be looking at. I do want to mention that we have done flow cytometry, and so far we have not seen any effect of vitamin E on the percentage of T-cells or B-cells. It doesn't mean that Th1 and Th2 are not being affected, and in fact some of our cytokine data indicate that perhaps that will be affected, but the total number of cells, you know the CD3s and so forth, is not affected by vitamin E supplementation. Neither is the total immunoglobulin level. So, the specific response to the vaccine is affected but not the total immunoglobulin level. 3   FOS is a nuclear protooncogene protein, also characterized as an immediate early gene product because of the time of its expression in relation to the cell cycle. FOS transcription is stimulated by injury. 4   AP1 is a transcription factor known to play a key role in the regulation of transcription of IL-2 and some other immune responses.

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