Micronutrient supplementation and T cell-mediated immune responses in patients with tuberculosis in Tanzania.

Limited studies exist regarding whether incorporating micronutrient supplements during tuberculosis (TB) treatment may improve cell-mediated immune response. We examined the effect of micronutrient supplementation on lymphocyte proliferation response to mycobacteria or T-cell mitogens in a randomized trial conducted on 423 patients with pulmonary TB. Eligible participants were randomly assigned to receive a daily dose of micronutrients (vitamins A, B-complex, C, E, and selenium) or placebo at the time of initiation of TB treatment. We found no overall effect of micronutrient supplements on lymphocyte proliferative responses to phytohaemagglutinin or purified protein derivatives in HIV-negative and HIV-positive TB patients. Of HIV-negative TB patients, the micronutrient group tended to show higher proliferative responses to concanavalin A than the placebo group, although the clinical relevance of this finding is not readily notable. The role of nutritional intervention in this vulnerable population remains an important area of future research.

Interleukin-1-induced anorexia in the rat. Influence of prostaglandins.

The anorexia associated with acute and chronic inflammatory or infectious conditions is poorly understood. Our objectives were to explore the anorexigenic effects of interleukin-1 (IL-1) in the rat. Recombinant human (rh) IL-1 beta, murine (rm) IL-1 alpha and to a lesser extent rhIL-1 alpha significantly reduced food intake at greater than or equal to 4.0 micrograms/kg i.p. but not at lower doses, in young (200-250 g) meal-fed rats on chow diets. The anorexic effect appears to be mediated by prostaglandins since pretreatment with ibuprofen completely blocked it, and a fish oil based diet abolished it, in comparison to corn oil or chow diets. Fish oil feeding also decreased basal and IL-1 stimulated prostaglandin E2 production by tissues in vitro (liver, brain, peritoneal macrophages) and in the whole body. Constant intravenous infusions of lower doses of IL-1 also diminished food intake, though intravenous boluses did not (reflecting rapid renal clearance). Chronic daily administration of IL-1 caused persistent inhibition of food intake for 7-17 d in chow and corn oil fed rats, but had no effect in fish oil fed rats. There was an attenuation of the effect (tachyphylaxis) after 7 d in corn oil and chow fed rats, but slowed weight gain and lower final weights were observed after 17-32 d of daily IL-1. Old (18-20 mo Fisher 344) rats showed less sensitivity to IL-1 induced anorexia. In conclusion, IL-1 is anorexigenic in the rat, but this is influenced by the structural form of IL-1, the route and chronicity of administration, the source of dietary fat, and the age of the animal. The ability of prior fat intake to influence the anorexic response to IL-1 represents a novel nutrient-nutrient interaction with potential therapeutic implications.

Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment.

Reductions in dietary fat, saturated fat, and cholesterol have been recommended to reduce the risk of heart disease in our society. The effects of these modifications on human cytokine production and immune responses have not been well studied. 22 subjects > 40 yr of age were fed a diet approximating that of the current American (14.1% of calories as saturated fatty acids, [SFA], 14.5% monounsaturated fatty acids [MUFA], 6.1% [n-6] polyunsaturated fatty acids [PUFA], 0.8% [n-3] PUFA, and 147 mg cholesterol/1,000 calories) for 6 wk, after which time they consumed (11 in each group) one of the two low-fat, low-cholesterol, high-PUFA diets based on National Cholesterol Education Panel (NCEP) Step 2 recommendations (4.0-4.5% SFA, 10.8-11.6% MUFA, 10.3-10.5% PUFA, 45-61 mg cholesterol/1,000 calories) for 24 wk. One of the NCEP Step 2 diets was enriched in fish-derived (n-3) PUFA (low-fat, high-fish: 0.54% or 1.23 g/d eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] [121-188 g fish/d]) and the other low in fish-derived (n-3) PUFA (low-fat, low-fish [0.13% or 0.27 g/d EPA and DHA] [33 g fish/d]). Measurements of in vivo and in vitro indexes of immune responses were taken after each dietary period. Long-term feeding of low-fat, low-fish diet enriched in plant-derived PUFA increased blood mononuclear cell mitogenic response to the T cell mitogen Con A, IL-1 beta, and TNF production and had no effect on delayed-type hypersensitivity skin response, IL-6, GM-CSF, or PGE2 production. In contrast, the low-fat, high-fish diet significantly decreased the percentage of helper T cells whereas the percentage of suppressor T cells increased. Mitogenic responses to Con A and delayed-type hypersensitivity skin response as well as the production of cytokines IL-1 beta, TNF, and IL-6 by mononuclear cells were significantly reduced after the consumption of the low-fat, high-fish diet (24, 40, 45, 35, and 34%, respectively; P < 0.05 by two-tailed Student's t test except for IL-1 beta and TNF, which is by one-tailed t test). Our data are consistent with the concept that the NCEP Step 2 diet that is high in fish significantly decreases various parameters of the immune response in contrast to this diet when it is low in fish. Such alterations may be beneficial for the prevention and treatment of atherosclerotic and inflammatory diseases but may be detrimental with regard to host defense against invading pathogens.

Dietary supplementation with n-3 fatty acids suppresses interleukin-2 production and mononuclear cell proliferation.

We studied the in vitro production of interleukin-2 in nine healthy volunteers who added 18 g/day of fish-oil concentrate rich in n-3 polyunsaturated fatty acids to their normal Western diet for a period of 6 weeks. Interleukin-2 synthesis from stimulated peripheral blood mononuclear cells was suppressed from 6.2 ng/ml at baseline to 2.2 ng/ml 10 weeks after the end of n-3 fatty acid supplementation (65% decrease; P = .04). At the same time phytohemagglutinin-induced proliferation of mononuclear cells was suppressed by 70% from the presupplement level. Interleukin-2 production returned to the premedication level at the end of the studies. The results suggest that the effect of dietary n-3 fatty acids in some diseases may be mediated in part by decreased production of interleukin-2 and decreased mononuclear cell proliferation.

Effect of vitamin E on human aortic endothelial cell responses to oxidative injury.

Reactive oxygen species produced by the cells present in the arterial wall may cause oxidative damage to cellular components altering endothelial cell (EC) function. Changes in the EC function appear to play a key role in the pathogenesis of atherosclerosis. Human aortic endothelial cells (HAEC) were employed to investigate the protective role of vitamin E upon exposure of endothelial cells to oxidative stress in vitro. HAEC assimilate d-alpha-tocopherol from the media in a dose-dependent manner. Exposure of HAEC to 16.5 mM of the free radical generator 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH) for 16 h decreased cell viability (assessed by trypan blue exclusion) from 90 to 28%. HAEC preincubated with vitamin E at 15, 30, and 60 microM prior to the AAPH exposure resulted in a dose-dependent increase in resistance to oxidative stress and increased cell viability by 37, 66, and 85%, respectively. An increase in prostacyclin (PGI2) production by HAEC in response to AAPH exposure was correlated positively with cell damage and negatively with vitamin E concentration. Interleukin (IL)-1 production also increased in parallel with cell damage induced by AAPH. Vitamin E treatment significantly reduced IL-1 production after AAPH exposure. This modulatory role of vitamin E on HAEC function following exposure to an oxidative stress may reflect its antioxidant protection against lipid peroxidation.

In vitro supplementation with different tocopherol homologues can affect the function of immune cells in old mice.

Alpha-tocophorel (T) is the most common form of vitamin E inplasma and tissues. Alpha-T is also believed to be superior to its homologues beta-T, gamma-T, and delta-T in antioxidant activity. Biological activity of alpha-T has been intensively studied in a number of bodily systems. In contrast, the other homologues have received little attention beyond the evaluation of their relative antioxidant activity. We as well as others have previously shown that alpha-T can enhance cell- mediated immune function of aged animals and humans. Gamma-T is a principal form of vitamin E in the American diet and some cooking oils contain substantial amount of beta-T and delta-T. Thus it is of public health interest to compare their biological effects with than of alpha-t in various systems. In this study, we used an in vitro supplementation protocol to determine immunologic effects of these T homologues on murine splenocytes. The results showed that all four T homologues enhance both spontaneous and mitogen-stimulated lymphocyte proliferation (LP) and the maximal enhancement produced by them was of the same magnitude. The dose range to produce maximal enhancement varied with different homologues. The efficiency was in the order of beta-T approximately delta-T > alpha-T. Interestingly, at 50 (optimal for alpha-T) and 150 micromol/L, while alpha-T enhanced LP, all the other homologues inhibited LP. This inhibition was found to be due to their cytotoxicity at these levels. T homologues had a differential effect on interleukin (IL)-2 and prostaglandin (PG)E(2) production. IL-2 production by mouse splenocytes was not affected by alpha-T or beta-T, but was increased by gamma-T and delta-T. All T homologues, except for beta-T, inhibited PGE(2) alpha-T. Thus, all the T homologues enhance LP. However, the dose required to reach maximal enhancement varies among the homologues. On the other hand, they have a differential effect on IL-2 and PGE(2) production. The difference in nature and magnitude of the effect on immune function does not correlate with their reported relative antioxidant activity and might be due to minor differences in their structure important to their other biological activities.

Immunologic effects of yogurt.

Many investigators have studied the therapeutic and preventive effects of yogurt and lactic acid bacteria, which are commonly used in yogurt production, on diseases such as cancer, infection, gastrointestinal disorders, and asthma. Because the immune system is an important contributor to all of these diseases, an immunostimulatory effect of yogurt has been proposed and investigated by using mainly animal models and, occasionally, human subjects. Although the results of these studies, in general, support the notion that yogurt has immunostimulatory effects, problems with study design, lack of appropriate controls, inappropriate route of administration, sole use of in vitro indicators of the immune response, and short duration of most of the studies limit the interpretation of the results and the conclusions drawn from them. Nevertheless, these studies in toto provide a strong rationale for the hypothesis that increased yogurt consumption, particularly in immunocompromised populations such as the elderly, may enhance the immune response, which would in turn increase resistance to immune-related diseases. This hypothesis, however, needs to be substantiated by well-designed randomized, double-blind, placebo-controlled human studies of an adequate duration in which several in vivo and in vitro indexes of peripheral and gut-associated immune response are tested.

Antioxidants and immune response in aged persons: overview of present evidence.

The oxidant-antioxidant balance is an important determinant of immune cell function, including maintaining the integrity and functionality of membrane lipids, cellular proteins, and nucleic acids and controlling signal transduction and gene expression in immune cells. Optimal amounts of antioxidants are needed for maintenance of the immune response across all age groups. This need might be more critical, however, in aged persons. Age-associated dysregulation of immune response, particularly of T cell-mediated function, is well documented. The well-known age-related increase in free radical formation and lipid peroxidation contributes, at least in part, to this phenomenon. We summarize animal and human studies undertaken by ourselves as well as other investigators on the effects of antioxidants, vitamin E, beta-carotene, and glutathione on the immune response of aged persons. The underlying mechanisms for the antioxidant nutrients' effects as well as their health implications for aged persons are discussed.

Altered lipoprotein metabolism in spontaneous vitamin E deficiency of owl monkeys.

Certain owl monkeys (AOT) develop spontaneous hemolytic anemia that responds to vitamin E. The anemia is associated with red blood cell lipid peroxidation and altered red blood cell membrane lipid composition. To investigate these changes, plasma lipid and lipoprotein profiles were characterized in anemic, anemia-susceptible, and anemia-resistant AOT. The plasma vitamin E and vitamin A concentrations were assessed as an index of fat absorption and the effect of corn oil supplementation and vitamin E-selenium injection were measured. Anemia-susceptible AOT had depressed plasma levels of vitamin E and A and an altered lipoprotein metabolism characterized by elevated ratios of low/high density lipoprotein cholesterol and free to esterified cholesterol in these lipoproteins. Vitamin E-selenium injection in anemia-susceptible AOT increased the plasma vitamin E, and vitamin E and corn oil supplements reduced the high density lipoprotein free to esterified cholesterol ratio. The data suggest that the AOT suffer from fat malabsorption and that the consequences (including tocopherol deficiency) result in altered cholesterol metabolism.

Assessment of the safety of high-dose, short-term supplementation with vitamin E in healthy older adults.

The effect of daily supplementation of 800 mg dl alpha-tocopheryl acetate for 30 d on general health, nutrient status, hepatic and renal function, intermediary metabolism, hematological status, plasma nutrients and antioxidant status, thyroid hormones, and urinary creatinine concentrations was studied in 32 healthy elderly (> 60 y) people who participated in a double-blind, placebo-controlled, residential trial. The subjects reported no side effects due to the supplements. Supplementation had no effect on body weight, plasma total protein, albumin, glucose, total cholesterol and triglycerides, conjugated and unconjugated bilirubin, alkaline phosphatase, indicators of hepatic and renal function, hematologic status, thyroid hormones, or serum and urinary creatinine concentrations and creatinine clearance. Supplementation did cause a significant increase in serum vitamin E, and a small (5%) but significant (P < 0.05) increase in plasma zinc in the vitamin E-supplemented group. Thus, short-term supplementation with 800 mg vitamin E/d has no adverse effect on healthy older adults.

Immunologic effects of marine- and plant-derived n-3 polyunsaturated fatty acids in nonhuman primates.

The effect of marine- and plant-derived n-3 polyunsaturated fatty acids (PUFAs) on T cell-mediated immune response was studied in cynomolgus monkeys. Animals were first fed a 14-wk baseline diet; 10 animals were then fed diets containing 1.3% or 3.3% of energy as eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) which the other 10 were fed diets containing 3.5% or 5.3% of energy as alpha-linolenic acid (ALA) for two consecutive 14-wk periods. Both diets significantly decreased the percentage of T cells (except 1.3% EPA + DHA), T helper cells (except 1.3% EPA + DHA and 3.5% ALA), and T suppressor cells. Proliferative response of lymphocytes to T cell mitogens significantly increased after the diet containing 3.3% EPA + DHA. Interleukin 2 production significantly increased after the diets containing 1.3% and 3.3% EPA + DHA. No significant changes in mitogenic response or interleukin 2 production were found after ALA diets. Feeding 1.3% or 3.3% EPA + DHA or 5.3% ALA significantly suppressed prostaglandin E2 production in response to T cell mitogens. Plasma tocopherol concentrations were decreased significantly only in monkeys fed ALA diets. We conclude that after adjustment for the tocopherol concentration, marine-derived n-3 PUFAs but not plant-derived n-3 PUFAs increased T cell-mediated mitogenic response and interleukin 2 production. This is most likely due to diet-induced quantitative differences in cellular fatty acid composition and, thus, in prostaglandin E2 production and tocopherol status.

Carotenoid and tocopherol concentrations in plasma, peripheral blood mononuclear cells, and red blood cells after long-term beta-carotene supplementation in men.

To determine the effects of long-term beta-carotene supplementation on concentrations of carotenoids and tocopherols in plasma and in blood cells, fasting blood was collected from 73 randomly selected physicians from the Boston area who are participating in the Physicians Health Study (PHS). The PHS is a randomized, placebo-controlled, double-blind study. In 1982, 22,071 male physicians were assigned to one of four treatments (325 mg aspirin alone, 50 mg beta-carotene alone, both, or neither) every other day. Plasma, peripheral blood mononuclear cells (PBMCs), and red blood cells (RBCs) from physicians who have participated in the study for approximately 12 y were analyzed for carotenoids and tocopherols. Compared with the placebo group, the supplemented group had higher beta-carotene concentrations in plasma (1.73+/-0.16 compared with 0.54+/-0.06 micromol/L0, RBCs (91.5+/-9.7 compared with 31.2+/-4.2 pmol/g hemoglobin), and PBMCs (61.6+/-10.3 compared with 15.5+/-2.5 pmol/10(7) cells). There were no differences in other carotenoids or tocopherols in plasma, RBCs, and PBMCs between these two groups. The beta-carotene concentrations. Plasma cryptoxanthin correlated with both RBC and PBMC cryptoxanthin concentrations but plasma lycopene correlated only with PBMC lycopene concentrations. These data suggest that plasma may not be the best indicator of carotenoid status. Furthermore, long-term beta-carotene supplementation in men results in higher beta-carotene concentrations in plasma, RBCs and PBMCs without lowering concentrations of other carotenoids or tocopherols.

Effect of vitamin E supplementation on prostaglandin concentrations in aspirin-induced acute gastric injury in aged rats.

Nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin, frequently cause gastric mucosal injury in the elderly. Impairment of prostaglandin synthesis is a crucial step by which aspirin attenuates mucosal defense capacity. Vitamin E has been shown to decrease prostanoid concentrations, which implies an ulceropermissive effect of vitamin E. To assess the effect of vitamin E on aspirin-induced gastric injury and mucosal prostanoid concentrations, 20 male rats aged 20 mo were divided into two groups and fed diets containing either 30 (physiologic requirement) or 500 mg all-rac-alpha-tocopheryl acetate/kg. After 6 wk, all rats received two intragastric doses of aspirin (1.4 mumol/kg body wt). A third group of six animals fed the high-vitamin E diet received a vehicle solution without aspirin. Mucosal samples for vitamin E and prostaglandin E2, 6-keto-prostaglandin F1 alpha, and thromboxane A2 measurements were collected. The prevalence and degree of mucosal lesions were not significantly different among all groups. Rats fed the high-vitamin E diet had significantly higher mucosal vitamin E concentrations than rats fed the low-vitamin E diet. Mucosal concentrations of all three prostanoids were 95% lower in aspirin-treated rats than in controls (P = 0.0001 in all instances). The high-vitamin E diet group had significantly lower mucosal 6-keto-prostaglandin F1 alpha concentrations (P = 0.02) than the low-vitamin E diet group, indicating decreased prostacyclin formation, whereas concentrations of prostaglandin E2 and thromboxane A2 were similar in the aspirin-treated groups. Aspirin markedly reduced mucosal prostanoid concentrations in rats, without apparent effects on gastric injury, whereas vitamin E supplementation significantly reduced mucosal 6-keto-prostaglandin F(1 alpha) concentrations. Nevertheless, vitamin E supplementation did not result in more gastric injury in aspirin-treated rats than in controls.

Beta-carotene-induced enhancement of natural killer cell activity in elderly men: an investigation of the role of cytokines.

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

Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects.

The effect of vitamin E supplementation on the immune response of healthy older adults was studied in a double-blind, placebo-controlled trial. Subjects (n = 32) resided in a metabolic research unit and received placebo or vitamin E (800 mg dl-alpha-tocopheryl acetate) for 30 d. Alpha-tocopherol content of plasma and peripheral blood mononuclear cells (PBMCs), delayed-type hypersensitivity skin test (DTH), mitogen-stimulated lymphocyte proliferation, as well as interleukin (IL)-1, IL-2, prostaglandin (PG) E2, and serum lipid peroxides were evaluated before and after treatment. In the vitamin E-supplemented group 1) alpha-tocopherol content was significantly higher (p less than 0.0001) in plasma and PBMCs, 2) cumulative diameter and number of positive antigen responses in DTH response were elevated (p less than 0.05), 3) IL-2 production and mitogenic response to optimal doses of concanavalin A were increased (p less than 0.05), and 4) PGE2 synthesis by PBMCs (p less than 0.005) and plasma lipid peroxides (p less than 0.001) were reduced. Short-term vitamin E supplementation improves immune responsiveness in healthy elderly individuals; this effect appears to be mediated by a decrease in PGE2 and/or other lipid-peroxidation products.

Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults.

The effect of vitamin B-6 deficiency on immune response was studied in eight healthy elderly adults. The protocol consisted of a 5-d baseline (BL) period; a vitamin B-6-depletion period of less than or equal to 20 d; three stages of vitamin B-6-repletion, each lasting 21 d; and a 4-d final phase. The amounts of vitamin B-6 ingested during the different phases of the study were 3.00, 15.00, 22.50, and 33.75 micrograms.kg body wt-1.d-1, respectively. During the final phase the subjects ingested 50 mg vitamin B-6/d. Fasting blood was collected at the end of each period. Vitamin B-6 depletion significantly decreased percentage and total number of lymphocytes, mitogenic responses of peripheral blood lymphocytes to T- and B-cell mitogens, and interleukin 2 production. These indices returned to BL values after the third vitamin B-6-repletion period, when the total vitamin B-6 intakes were 1.90 +/- 0.18 mg/d for women and 2.88 +/- 0.17 mg/d for men. Vitamin B-6 deficiency impairs in vitro indices of cell-mediated immunity in healthy elderly adults. This impairment is reversible by vitamin B-6 repletion.

Short- and long-term beta-carotene supplementation do not influence T cell-mediated immunity in healthy elderly persons.

Supplementation of healthy elderly persons with beta-carotene has been considered a way to enhance immune responses. In study 1 the short-term effect of beta-carotene (90 mg/d for 3 wk) on immunity was assessed in a randomized, double-blind, placebo-controlled longitudinal comparison of healthy elderly women. In study 2 the long-term effect of beta-carotene (50 mg every other day for 10-12 y) on immunity was assessed in a randomized, double-blind, placebo-controlled longitudinal comparison of men enrolled in the Physicians' Health Study. Subjects from both studies taking active supplements had significantly greater plasma beta-carotene concentrations than did subjects taking placebo. The pre- to postintervention change in delayed-type hypersensitivity skin test responses between beta-carotene and placebo groups in the short-term study was not significantly different, nor was the response between treatment groups in the long-term study. There were no significant effects due to beta-carotene supplementation on in vitro lymphocyte proliferation, production of interleukin 2, or production of prostaglandin E2 as a result of short- or long-term beta-carotene supplementation. In addition, there were no differences in the profiles of lymphocyte subsets [total T cells (CD3+), T helper cells (CD4+), T cytotoxic-suppressor cells (CD8+), and B cells (CD19+)] due to short- or long-term beta-carotene supplementation, nor were there differences in percentages of CD16+ natural killer cells or activated lymphocytes (cells expressing interleukin 2 transferrin receptor) due to long-term beta-carotene supplementation. Consistent results from these two trials show that beta-carotene supplementation did not have an enhancing or suppressive effect on T cell-mediated immunity of healthy elderly.

Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults.

We showed previously that supplementation for 30 d with 800 IU (727 mg) vitamin E/d did not adversely affect healthy elderly persons. We have now assessed the effects of 4 mo of supplementation with 60, 200, or 800 IU (55, 182, or 727 mg) all-rac-alpha-tocopherol/d on general health, nutrient status, liver enzyme function, thyroid hormone concentrations, creatinine concentrations, serum autoantibodies, killing of Candida albicans by neutrophils, and bleeding time in 88 healthy subjects aged >65 y participating in a double-blind, placebo-controlled trial. No side effects were reported by the subjects. Vitamin E supplementation had no effect on body weight, plasma total proteins, albumin, glucose, plasma lipids or the lipoprotein profile, total bilirubin, alkaline phosphatase, serum aspartate aminotransferase, serum alanine aminotransferase, lactate dehydrogenase, serum urea nitrogen, total red blood cells, white blood cells or white blood cell differential counts, platelet number, bleeding time, hemoglobin, hematocrit, thyroid hormones, or urinary or serum creatinine concentrations. Values from all supplemented groups were within normal ranges for older adults and were not significantly different from values in the placebo group. Vitamin E supplementation had no significant effects on plasma concentrations of other antioxidant vitamins and minerals, glutathione peroxidase, superoxide dismutase, or total homocysteine. There was no significant effect of vitamin E on serum nonspecific immunoglobulin concentrations or anti-DNA and anti-thyroglobulin antibodies. The cytotoxic ability of neutrophils against Candida albicans was not compromised. Thus, 4 mo of supplementation with 60-800 IU vitamin E/d had no adverse effects. These results are relevant for determining risk-to-benefit ratios for vitamin E supplementation.

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

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.

Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects.

BACKGROUND: We have shown that the age-associated increase in prostaglandin E(2) production contributes to the decline in T cell-mediated function with age. Black currant seed oil (BCSO), rich in both gamma-linolenic (18:3n-6) and alpha-linolenic (18:3n-3) acids, has been shown to modulate membrane lipid composition and eicosanoid production. OBJECTIVE: Our objectives were to 1) test whether dietary supplementation with BCSO can improve the immune response of healthy elderly subjects, and 2) determine whether the altered immune response is mediated by a change in the factors closely associated with T cell activation. DESIGN: A randomized, double-blind, placebo-controlled (soybean oil) study was conducted to examine the effect of 2 mo of BCSO supplementation on the immune response of 40 healthy subjects aged >/=65 y. In vivo immune function was determined by delayed-type hypersensitivity skin response. Peripheral blood mononuclear cells (PBMCs) were tested for in vitro immune response. RESULTS: In subjects supplemented with BCSO, the total diameter of induration at 24 h and individual responses to tetanus toxoid and Trichophyton mentagrophytes were significantly higher than their baseline values. The change in response to tetanus toxoid was significantly different from that of the placebo group. The BCSO group showed a significant increase in proliferative response of PBMCs to the T cell mitogen phytohemagglutinin that was not significantly different from that observed in the placebo group. BCSO had no effect on concanavalin A-induced mitogenic response, interleukin 2 and -1beta production, and PBMC membrane fluidity. Prostaglandin E(2) production was significantly reduced in the BCSO-supplemented group, and this change was significantly different from that of the placebo group. CONCLUSION: BCSO has a moderate immune-enhancing effect attributable to its ability to reduce prostaglandin E(2) production.