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Effect of Concomitant Consumption of Fish Oil and Vitamin E on T Cell Mediated Function in the Elderly: A Randomized Double-Blind Trial

The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts

Address reprint requests to: Simin Nikbin Meydani, Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: simin.meydani{at}tufts.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Objectives: To determine if concomitant consumption of fish oil and vitamin E would modify the vitamin E level needed for improving T cell mediated function in elderly.

Methods: A randomized and double-blind study was conducted using 40 healthy male and female elderly subjects (>65 y) who were randomly assigned to one of 4 groups (n = 10/group). All the subjects received 5 g of fish oil daily containing 1.5 g eicosapentaenoic acid (EPA) and 1 g docosahexaenoic acid (DHA), and a capsule containing different doses of dl--tocopherol (0, 100, 200 or 400 mg/day) for 3 mo. Plasma vitamin E and fatty acid levels, and in vivo [delayed-type hypersensitivity skin response (DTH) and T cell sub-population analysis] and ex vivo [mitogen-stimulated peripheral blood mononuclear cells (PBMC) proliferation and interleukin (IL)-2 production] immune functions were determined at baseline and after supplementation.

Results: The control group (fish oil only) did not show a statistically significant change in either DTH or PBMC proliferation. DTH response, however, was significantly increased from baseline in all groups supplemented with fish oil plus vitamin E and a significant positive correlation between DTH response and plasma concentrations of -tocopherol was observed. PBMC proliferation was only significantly increased in the group supplemented with fish oil plus 200 mg vitamin E. However, the changes caused by fish oil plus vitamin E in either DTH or PBMC proliferation were not significantly different from those observed in control group. Plasma levels of -tocopherol were significantly increased in all three fish oil plus vitamin E groups and the increase in plasma -tocopherol level was less profound than that previously reported when vitamin E was given alone.

Conclusions: The immuno-enhancing effect of vitamin E in the elderly is dampened when it is concomitantly consumed with fish oil. This may be due to the smaller increase in plasma concentrations of vitamin E in the presence of fish oil.

Key words: vitamin E, fish oil, n-3 fatty acids, immune function, aging

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Age-associated change in immune function is well documented in numerous human and animal studies [1–3]. Dysregulated immune response contributes to higher morbidity and mortality from infectious, neoplastic, and inflammatory diseases in the elderly compared to young subjects [2,4].

Vitamin E is a potent peroxyl radical scavenger and serves as a chain-breaking antioxidant to prevent biological membranes from oxidative damage [5]. While vitamin E deficiency is rare in well-nourished healthy subjects, supplementation beyond the current daily requirement has been shown to enhance immune function in the aged. Supplementing the diet of old mice with vitamin E significantly increased delayed-type hypersensitivity (DTH) response, lymphocyte proliferation, and interleukin (IL)-2 production [6]. In vitro addition of vitamin E was also shown to increase proliferation and IL-2 production by splenocytes [7], purified mouse T cells [8,9], and naïve T cells [9] from old mice. In elderly subjects, dietary vitamin E supplementation was shown to enhance T cell mediated function including DTH response, antibody production in response to vaccination, lymphocyte proliferation, and IL-2 production [10,11] and to reduce the risk for acquiring respiratory infections [12].

Epidemiological and several clinical trials have indicated that consumption of fish and fish oil supplements might reduce the risk of cardiovascular and inflammatory diseases [13–15], the incidence of which increase with age. Thus, the elderly are often encouraged to consume more fish or fish oil. However, consumption of large amounts of fish or fish oil supplements could affect cell-mediated immunity as well as inflammatory responses. While some studies reported no effect or enhancing effect of fish oil on T cell mediated function, a majority of studies have demonstrated a suppressive effect of fish oil consumption on T cell mediated immune responses (reviewed by Calder et al. [16]).

In most studies, the immuno-enhancing effect of vitamin E was investigated when vitamin E was added to the standard diet of animals or provided to human subjects who consumed a typical Western diet in which n-3 fatty acids are low. Few studies have examined the impact of vitamin E supplementation on immune system when it is consumed with fish oil. Since fish oils contain a high level of n-3 polyunsaturated fatty acids, which have been shown to reduce the plasma level of supplemental vitamin E [17], the current study was conducted to determine the effect of concomitant consumption of fish oil and vitamin E on T cell mediated immune responses in healthy elderly subjects. In addition, since our previous dose response study indicated that 200 mg/day provided the optimal level of vitamin E for improving the immune response in the elderly [11], we wanted to determine if a higher intake of fish oil would modify the vitamin E level needed for improving the immune response in the elderly.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Subjects and Experimental design
Subjects were recruited following the institutional protocols as previously described [18]. Those who were: non-smokers; not suffering from acute or serious chronic diseases; not taking prescription medication or non-steroidal anti-inflammatory drugs on a regular basis; not taking vitamin, mineral, or lipid supplements for the last month were included in the study after a standard screening procedures as previously described [18]. All the enrolled subjects were healthy free-living older adults (65 y) of both sexes. The study protocol was approved by the Tufts University/New England Medical Center Human Investigation Review Committee. In this double-blind, placebo-controlled (for vitamin E) protocol, subjects were randomly assigned to one of the four groups (10 subjects/group). The baseline subject characteristics are given in Table 1. The subjects in Group 1 were given 5 capsules/d of Omega-500^TM fish oil (Omega Caps, St. Louis, MO) and a placebo capsule for vitamin E (soybean oil). The subjects in Group 2, 3, and 4 were given 5 capsules/d of Omega-500^TM and a capsule/d containing 100, 200, or 400 mg of vitamin E (dl--tocopherol in soybean oil, Hoffmann-LaRoche, Nutley, NJ), respectively. Each Omega-500^TM fish oil capsule weighs 1 g and contains 300 mg eicosapentaenoic acid (EPA), 200 mg docosahexaenoic acid (DHA), and 1 IU of vitamin E as dl--tocopheryl acetate. The total amount of fat provided by supplements was 5 g, or 2.2 to 2.5% of total daily energy intake of subjects as calculated from 3-day dietary records (see below). The subjects consumed the capsules daily for 3 mo while continuing their typical food intake, dietary habits, and lifestyle. To assure that no substantial change in dietary habits had occurred during the study, each subject completed two 3-day dietary records, one during the first month of the study and the other one during the last month of the study. An adequate number of capsules were given to subjects on days 11, 51, and 81 of the study. Subjects received a compliance reminder telephone call every two weeks. Compliance was monitored by pill count and monthly measurement of plasma fatty acids. The subjects and investigators were blinded with regard to vitamin E supplementation. Subjects were required to abstain from taking any other supplements or any other medication during the study period without consulting the investigators.

Delayed-Type Hypersensitivity Skin Response
DTH was assessed with Multi-Test CMI (Merieux Institute Inc., Miami, FL), a single-use, disposable applicator of acrylic resin with 8 heads loaded with a glycerine control and the following 7 recall antigens: tetanus toxoid, diphtheria toxoid, streptococcus (group C), Mycobacterium tuberculosis, Candida albicans, Trichophyton mentagrophytes, and Proteus mirabilis as previously described. The diameters of positive reactions were measured by a caliper at 24 and 48 h after administration of the test. Detailed procedure was described previously [11,21].

Isolation of Mononuclear Cells
Forty milliliters of blood were collected in heparin-containing Vacutainers (Becton Dickinson, Rutherford, NJ) after a 14-h fast. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll-Paque (Pharmacia Biotech, Piscataway, NJ) density gradient centrifugation as previously described [18]. Cell viability was assessed using trypan blue exclusion. Cells were suspended in RPMI 1640 (Sigma, St. Louis, MO) supplemented with 100,000 U/L penicillin, 100 mg/L streptomycin (Gibco Laboratories, Grand Island, NY), 2 mmol/L L-glutamine (Gibco), 25 mmol/L HEPES (Sigma), and heat-inactivated autologous plasma at appropriate densities for different cultures.

Lymphocyte Proliferation
Lymphocyte proliferation was determined by incorporation of [³H]-thymidine following stimulation with T cell mitogens. PBMC at 1 x 10⁵ cells/well (0.2 mL) in complete RPMI 1640 with 5% autologous plasma were cultured in 96-well flat bottom plates (Becton Dickinson Labware, Lincoln Park, NJ), in the presence or absence of the T cell mitogens concanavalin A (Con A; Sigma) at 5, 10, 25, and 50 or phytohemagglutinin (PHA; Difco Laboratories, Detroit, MI) at 1, 5, 10, and 50 mg/L for 72 h at 37°C in an atmosphere of 5% CO₂ and 95% humidity. The optimal dose is 10 mg/L for both Con A and PHA. Cultures were pulsed with 18.5 µBq of [³H]-thymidine (specific radioactivity 247.9 GBq/mol; DuPont NEN Products, Boston, MA) during the final 4 h of incubation. The cells were harvested onto glass fiber filter mats (Wallac, Gaithersburg, MD) by a Tomtec harvester (Wallac) and cell proliferation was quantified as the amount of [³H]-thymidine incorporation into DNA as determined by liquid scintillation counting in a 1205 Betaplate counter (Wallac).

IL-2 Production
PBMC at 1 x 10⁶ cells/well (1 mL) in complete RPMI 1640 with 9% autologous plasma were cultured in 24-well flat bottom plates (Becton Dickinson Labware) in the presence or absence of Con A or PHA at 50 mg/L for 48 h. Cell-free supernatants were analyzed for IL-2 activity using the bioassay method described by Gillis et al. [22]. Briefly, the samples, in graded dilutions, were cultured with cytotoxic T lymphocyte line 2 (CTLL-2) cells for 24 h. Cultures were pulsed by adding 18.5 µBq of [³H]-thymidine during the last 6 h before they were harvested. Recombinant IL-2 (Genzyme) was used as the standard. One unit per milliliter is defined as the amount of recombinant IL-2 that causes a half-maximal incorporation of [³H]-thymidine into 5 x 10³ CTLL-2 cells.

Lymphocyte Subsets
Lymphocyte subsets were determined by flow cytometry as described previously [21]. Briefly, 5 x 10⁵ PBMC cells were stained for 30 min on ice with fluorescein (FITC)- or phycoerythrin (PE)-conjugated monoclonal antibodies (Becton Dickinson, San Jose, CA) to total T cells (Leu 4, Anti-CD3), T-helper cells (Leu 3, Anti-CD4), T-cytotoxic/suppressor cells (Leu 2, Anti-CD8), and B cells (Leu 12, Anti-CD 19). Cytometric analysis was conducted using a flow cytometer (FACScan, Becton Dickinson).

Statistical Analysis
The sample size was determined using variability observed in our previous studies and expected difference in DTH and lymphocyte proliferation assay [20,21] as described by Snedcor [23]. Data within each group were analyzed by paired Student’s t test using SYSTAT statistical package (SYSTAT 9.0, SYSTAT, Inc., Evanston, IL). The comparison of changes among groups was conducted using ANOVA for the overall effect of vitamin E supplementation, followed by Tukey’s test for individual comparisons between groups. Significance was set at P < 0.05. Data are presented as mean ± SE.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Plasma Fatty Acid Composition and Vitamin E Levels
There was no significant difference in baseline age and body mass index (BMI) among the groups (Table 1). BMI did not change significantly after supplementation in any group (data not shown). There was no significant difference in biochemical profiles of both blood and urine among the groups at baseline or after 3 mo supplementation (data not shown). There was no statistically significant difference in fatty acid profiles among the groups at baseline. A significant increase in plasma levels of EPA and DHA was observed after the supplementation with fish oil (Table 2). While arachidonic acid (AA, 20:4, n-6) levels decreased in all groups, a statistically significant decrease in AA levels was observed only when all groups were pooled for the fish oil effect (7.30 ± 0.29% at baseline to 6.36 ± 0.23% after 3 mo supplementation, p < 0.01). There was no significant change in linoleic acid [LA (18:2,n-6)]. Levels of total saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) were not significantly changed.

View larger version (12K): [in this window] [in a new window]   Fig. 1. Correlation between plasma vitamin E and delayed-type hypersensitivity skin response. Healthy elderly subjects were supplemented with fish oil and different levels of vitamin E for 3 mo. Plasma samples were collected to determine the vitamin E concentrations using HPLC and DTH was assessed with a Multi-Test CMI, as described in the method section. Data are the post-supplementation measures from 34 subjects. There is a significant correlation (r = 0.565, p < 0.01) between the plasma -tocopherol concentrations and DTH responses (total maximal induration).

View larger version (18K): [in this window] [in a new window]   Fig. 2. Effect of dietary supplementation with fish oil and different levels of vitamin E on lymphocyte proliferation. Peripheral blood mononuclear cells (1 x 105) were stimulated with concanavalin A (Con A) or phytohemagglutinin (PHA) at 10 mg/L for 72 h and pulsed with [3H]thymidine during the last 4 h to determine DNA synthesis. Proliferation levels are expressed as average counts per minute (cpm). The unstimulated cells had a background count ranging from 70 to 100 cpm, which did not change after the supplementation. Data are mean ± SE, n = 8 to 10/group. * Significantly different from baseline at p < 0.05 (Student’s paired t test).

Lymphocyte Sub-Populations
There was no significant difference among the groups at baseline or after 3 mo supplementation in the values of red blood cells, platelets, total white blood cells and their differentials, or lymphocyte sub-populations bearing markers CD3 (total T cells), CD4 (helper T cells), CD8 (cytotoxic/suppressor T cells), and CD19 (B cells) (data not shown).

	DISCUSSION

 
The purpose of this study was to define whether the previously established immuno-enhancing effect of vitamin E in the elderly is modified by the concomitant intake of a fish oil supplement, and if so, whether this would influence the optimal dose needed for the vitamin E-induced immune enhancement. The results from this study indicate that while consumption of vitamin E improves T cell mediated immune function in the elderly subjects as indicated by increased DTH and ex vivo mitogen-stimulated lymphocyte proliferation, the changes observed are quantitatively less when elderly subjects consumed fish oil compared to previous studies in which subjects were supplemented with vitamin E alone [10,11]. One limitation of the current study is that we did not have a positive control group receiving vitamin E and no fish oil. However, in two previous studies we demonstrated that vitamin E significantly improves cell-mediated immune response in elderly people [10,11]. In recruiting the participants for the current study, we used the same exclusion/inclusion criteria as those in the previous studies. Furthermore, all these studies used the same methods and techniques. Comparison of baseline characteristics of the subjects in the current study with those in our previous study supports the similarity of populations [10,11].

In this study, the change in either diameter of DTH test (total induration) or mitogen-stimulated T cell proliferation was not significantly different between the placebo group and any of the vitamin E groups. However, compared to their own baseline levels significant improvements were observed in all the vitamin E supplemented groups for DTH test, and in the 200 mg/d vitamin E group for lymphocyte proliferation. Furthermore, as can be seen in Fig. 1, the degree of changes in plasma -tocopherol levels to a given dose of vitamin E varies by subject, and is positively correlated with the magnitude of DTH response, which supports our previous findings [10,11]. In contrast to the previous studies in which subjects did not consume additional fish oil [10,11], in this study, there is no difference in plasma vitamin E levels between the 3 vitamin E supplemented groups (Table 3), suggesting that the less significant immunoenhancing effect of vitamin E may be due to altered supplementation efficacy resulting from concomitant fish oil intake.

Thus, to determine the reason for the lower immuno-stimulatory effect of vitamin E in this study, we compared changes in plasma vitamin E levels and DTH from this study with those observed in our previous study in which subjects consumed 200 mg/d vitamin E alone [11]. In that study, the subjects consuming 200 mg/d for 4 mo exhibited 99% increase in plasma -tocopherol level, which corresponded to 65% increase in their DTH response. In the present study, the subjects consuming 200 mg/d vitamin E with 5 g/d of fish oil exhibited only 25% increase in plasma -tocopherol level and 30% increase in DTH response. The adverse effect of increased consumption of fish oil on plasma vitamin E levels has been observed by others. Yaqoob et al. [24] supplemented healthy adult subjects with 205 mg/d vitamin E alone or together with fish oil for 3 mo and reported a smaller increase in plasma vitamin E levels in the group consuming fish oil plus vitamin E (from 26.1 to 36.9 µmol/L) compared to that in the group consuming vitamin E alone (from 25.7 to 46.3 µmol/L). Wander et al. [25] reported that daily consumption of 15 g fish oil together with 0, 100, 200, or 400 mg vitamin E for 5 wk increased plasma -tocopherol levels by 40%, 54%, and 63% in subjects supplemented with 100, 200, or 400 mg vitamin E, respectively, while no significant change was observed in the placebo group. Although the percent increases in the latter study are larger than those observed in our study (32, 25, and 36%, respectively for 100, 200, and 400 mg/d vitamin E groups), the absolute increases were smaller than those in the current study. This might be due to the lower baseline levels in the study by Wander et al. [25] compared to those of ours (18.5 vs. 25.7 to 30 µmol/L). It is plausible that the same doses of supplementation with vitamin E would cause a greater percent increase in plasma vitamin E levels in subjects with low baseline levels relative to those with higher baseline levels. In addition, the differences in subject characteristics between the two studies might have contributed to the different baseline levels as well as the reaction to the supplementation. The subjects in Wander’s study were postmenopausal women (45 to 70 y) and half of them were under hormone replacement therapy during the study while the subjects in our study were elderly men and women (65 y) not taking other supplements or medication. Although the increases in plasma -tocopherol levels were greater in Wander’s study compared to those in the current study, these increases were still smaller when compared to those of our earlier studies where vitamin E was consumed in the absence of fish oil [10,11].

Reduced bioavailability of vitamin E by concomitant consumption of fish oil has long been reported but the underlying mechanism is not well understood [26]. Meydani et al. [17] fed C57BL mice diets containing 5% fish, corn, or coconut oil, supplemented with 30 (control), 100, or 500 ppm vitamin E (dl--tocopheryl acetate) for 6 wk and compared their tissue levels of vitamin E. Compared with the mice fed 30 ppm vitamin E (control), the mice fed 100 and 500 ppm vitamin E showed increased plasma -tocopherol levels by 53% and 143% in the coconut oil group, 98% and 161% in the corn oil group, and 14% and 40% in the fish oil group, respectively. Similar patterns were observed in liver, kidney, and lung. Lower plasma levels of vitamin E were shown not to be due to oxidative loss of vitamin E in the diets. Rather, it was speculated to result from an interaction of fish oil and vitamin E at the gut level and/or enhanced post-absorptive utilization of vitamin E compared to mice fed coconut or corn oil.

In the current study, decreased levels of plasma -tocopherol were observed when the plasma -tocopherol concentrations were increased as a result of the dietary supplementation with different doses of dl--tocopherol. This reciprocal relationship between - and -tocopherols has been reported previously [10,25,27]. It indicates that plasma is preferentially enriched in - over -tocopherol. This is not due to a differential absorption of the different forms of vitamin E [28] but rather, it may be because the liver secrets VLDL particles preferentially enriched in -tocopherol [29].

Vitamin E supplementation has been shown to increase IL-2 production in elderly humans [10] and old animals [30]. However, we did not observe a significant change in IL-2 production in any group in the current study. The less dramatic increase in the plasma vitamin E and a possible counter effect from fish oil may account for the absence of this effect. On the other hand, although IL-2 is critical in T cell activation, an increase in its production is not the sole mechanism by which improved T cell proliferation or DTH response can be achieved. Consequently, an improved T cell response does not always correlate with higher IL-2 production. In another study, for example, an increased T cell proliferation without a significant change in IL-2 production has been observed with other dietary interventions [31]. These data suggest that the improvement in lymphocyte proliferation and DTH observed here are mediated through other post IL-2 mechanisms.

In summary, this study demonstrated that concomitant consumption of fish oil reduces the immuno-enhancing effect of vitamin E on T cells in the elderly. This effect of fish oil might be due to lower plasma levels achieved following vitamin E supplementation in the presence of fish oil. Further studies are needed to determine whether this lower level of plasma vitamin E results from reduced bioavailability of vitamin E and/or increased consumption of vitamin E in cellular metabolism when fish oil are concomitantly consumed.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
The authors would like to thank the volunteers who participated in this study as well as the nurses and staff of the Metabolic Research Unit, the Dietary Assessment Unit, and the Nutritional Evaluation Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University for their invaluable efforts. The authors would also like to thank Robert Loszewski for the help with immunological tests and Stephanie Marco for the preparation of the manuscript.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Supported by the NIH grant RO1 AG11020 and the US Department of Agriculture, Agriculture 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.

Received December 12, 2004. Accepted December 20, 2005.

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TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 

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