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Nutritional Immunology

Immunity and Antioxidant Capacity in Humans Is Enhanced by Consumption of a Dried, Encapsulated Fruit and Vegetable Juice Concentrate¹

Food Science and Human Nutrition Department University of Florida Gainesville, Florida 32611

^* To whom correspondence should be addressed. E-mail: percival{at}ufl.edu.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
The daily consumption of fruits and vegetables is a common dietary recommendation to support good health. We hypothesized that a commercially available encapsulated fruit and vegetable juice powder concentrate (FVJC) could support functional indices of health due to increased intake of various phytonutrients. This was a double-blind, randomized, placebo-controlled investigation of 59 healthy law students who consumed either FVJC or placebo capsules for 77 d. Blood was collected on d 1, 35, and 77 to examine the number of circulating ß- and -T cells, cytokine production, lymphocyte DNA damage, antioxidant status, and levels of carotenoids and vitamin C. A log of illnesses and symptoms was also kept. The FVJC group tended to have fewer total symptoms than the placebo group (P < 0.076). By d 77 there was a 30% increase in circulating -T cells and a 40% reduction in DNA damage in lymphocytes in the FVJC group relative to the placebo group. Plasma levels of vitamin C and of ß-carotene, lycopene, and lutein increased significantly from baseline in the FVJC group as did plasma oxygen radical absorptive capacity (50%). Interferon- produced by phorbol-stimulated lymphocytes was reduced 70% in the FVJC group, whereas other cytokines (IL-4, IL-6, transforming growth factor ß) were unchanged relative to treatment or time. FVJC consumption during this study period resulted in increased plasma nutrients and antioxidant capacity, reduction in DNA strand breaks, and an increase in circulating -T cells.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

An encapsulated fruit and vegetable juice concentrate (FVJC)³ has been shown to increase proliferation of peripheral blood mononuclear cells (PBMC), improve natural killer (NK) cell cytotoxicity in elderly nonsmokers, and increase IL-2 production in both smokers and nonsmokers (4). We hypothesized that consumption of this FVJC might also impact markers of immune function in a younger population, particularly related to the -T–cell population. -T cells, having characteristics of innate and acquired immunity, play a role in protecting epithelial linings, immunosurveillance against virally infected and tumor cells, and a role in wound healing (5–7). A previous study also found that FVJC consumption for 84 d reduced the amount of DNA damage in PBMC, as measured by the comet assay (4). Moreover, studies using this preparation showed that plasma carotenoids (4,8–12) and plasma vitamin C levels increase (9–11), whereas indicators of oxidative damage, such as serum lipid peroxide levels (12) and plasma malondialdehyde levels, decrease (11).

Our objective was to extend these studies and examine an otherwise healthy population that might be experiencing stress. Law students are reported to have reduced subjective well-being relative to the general population or to medical students (13). Subjective well-being refers to how people evaluate their lives. Law students have also been observed to acquire impairment in both psychological and physical health (14). Stress is known to have detrimental effects on immunity and may increase susceptibility to infectious agents, influence the severity of infections, reduce the response to vaccines, activate latent herpes or Epstein-Barr viruses, and reduce the rate of wound healing (15). The stress response resembles a pro-oxidative state with the potential for free radical damage to a number of cells and tissues.

We hypothesized that consumption of FVJC capsules could prevent damage to specific immune cells in these students. We measured the number of circulating T cells, cytokine secretion after culture, DNA strand breaks in lymphocytes, antioxidant status, and the number and duration of illnesses. Also evaluated was a marker for stress, Epstein-Barr virus (EBV) titers (16,17).

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Study design. Healthy men (n = 23) and women (n = 36), ranging in age from 21 to 53 y (mean 25 y), were recruited from the University of Florida's Levin College of Law in Gainesville, Florida, during August, 2004. Exclusion criteria included the use of tobacco products, chronic or excessive alcohol consumption, use of illegal pharmaceuticals, pregnant or lactating females, and recent surgery or illness. The study was conducted over an 11-wk period. The study was approved by the University of Florida's Institutional Review Board. Written informed consent was obtained from each subject.

On d 1, subjects were randomly assigned, in a double-blind fashion, to either the placebo group, who received capsules containing microcrystalline cellulose, or the FVJC group, who received capsules containing primarily fruit and vegetable juice powder concentrate derived from acerola cherry, apple, beet, broccoli, cabbage, carrot, cranberry, kale, orange, peach, papaya, parsley, pineapple, spinach, and tomato (Juice Plus+ NSA). The FVJC capsules provided 7.5 mg ß-carotene, 234 mg vitamin C, 45 IU vitamin E, 420 µg folate, 60 mg calcium, and about 42 kJ (9–11). Subjects were instructed to consume 4 capsules/d (2 in the morning and 2 in the evening) with meals and to otherwise not alter their habitual diet.

On d 77, when study participants arrived for their final blood draw, a questionnaire was used to evaluate compliance, efficacy of blinding, and intercurrent illness. Compliance was also assessed by the returned capsule count. Subjects gave detailed specific symptom information on running or congested nose, stiffness or chills, headache, cough, fever, sore throat, and aches. They noted the date of occurrence, duration of each particular symptom, whether medical treatment was sought, and if medication was prescribed. Symptoms refer to the sum of all of the symptoms for each person for all of their reported illnesses. Participants also provided their semester grade-point average at the end of the term.

    Plasma collection and analysis. Fasting blood was collected into 2 EDTA tubes on d 1, 35, and 77. One tube was placed at 4°C, one at room temperature, and both were processed within 1 h after collection. Plasma was removed from the 4°C blood and processed in relative darkness. After a 1:5 dilution was made in 6% m-phosphoric acid to preserve ascorbic acid, samples were frozen at –85°C. Aliquots of untreated plasma were frozen at –85°C for oxygen radical absorbance capacity (ORAC) assay, carotenoid profiling, and EBV antibody titer studies.

For PBMC separation, 7 mL of whole, anticoagulated blood held at room temperature was diluted 1:1 with 0.15 mol/L of NaCl. Six mL of the diluted blood was layered over 3 mL of Nycoprep 1.077 (Axis-Shield) and centrifuged (800 x g, 20 min, 20°C). The mononuclear cell layer was removed and washed twice with RPMI 1640 (Cellgro; Mediatech) complete (100,000 U/L penicillin; 100 mg/L streptomycin; 0.25 mg/L fungizone; 50 mg/L gentamycin; 2 mmol/L l-glutamine; 25 mmol/L HEPES buffer) containing 10% fetal bovine serum (Cellgro). Cell pellets were resuspended in RPMI 1640 complete.

    Flow cytometry. Percentages of ß- and -T–cell populations in whole PBMC suspensions were determined by 2-color flow cytometry on d 1 and 77. On the day of each blood draw, PBMC (5 x 10⁵) was incubated with phycoerythrin-labeled anti-human CD3⁺ and 1 of 2 T-cell surface markers: fluorescein isothiocyanate-labeled anti-human ß-TCR or fluorescein isothiocyanate-labeled anti-human -TCR; or with the CD3⁺ isotype control phycoerythrin-labeled anti-human IgG2a_K, (eBioscience) alone. Data collected was from gated CD3⁺ cells with fluorescence brighter than the nonspecific isotype control, and analyzed using WinMDI software (Scripps Institute).

    DNA strand break assay. An aliquot of PBMC (1 x 10⁹/L) in complete RPMI 1640 medium with 10% autologous plasma, were placed into 2 wells of a 12-well Falcon plate from d 1, 35, and 77. Hydrogen peroxide (H₂O₂) was added to 1 of the wells to a final concentration of 10 mmol/L, with the untreated well serving as control. The cells were incubated at 37°C for 2 h. Cells were washed once and processed using the ApoAlert DNA Fragmentation Assay Kit (BD Biosciences Clonetech). This assay is based on the terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay. Terminal deoxynucleotidyl transferase catalyzes the incorporation of fluorescein-dUTP at the free 3'-hydroxyl ends of fragmented DNA. The fluorescein-labeled DNA was quantified by flow cytometry. Data were analyzed using WinMDI software (Scripps Institute). Results are expressed as a ratio of DNA strand breaks in cells treated with H₂O₂ to untreated cells.

    Cytokine level determination in supernatants from cell proliferation. On samples from d 1 and 77, PBMC in RPMI 1640 complete medium containing 50 mmol/L 2-mercaptoethanol, 10% autologous plasma, 10 µg/L phorbol 12-myristate 13-acetate (PMA, Sigma) and 1,000,000 U/L recombinant human IL-2 (r-IL-2, BD Biosciences) was seeded (3 x 10⁵/200µL) into 8 wells of a 96-well U-bottom microtiter plate and incubated in a humidified 5% CO₂ atmosphere at 37°C. After 72 h, the media were removed, replaced with medium without PMA, and the cells were incubated for an additional 11 d. During this time, not only are ß-T cells stimulated to proliferate and produce cytokines, but the -T cells are also proliferating and stimulated. On d 14, supernatant fluids were frozen at –85°C. These conditions allow enough time for activation of both ß-T cells and -T cells. Accumulated levels of human INF-, IL-4, TGF-ß, and IL-6 in PBMC supernatants were quantified using ELISA (BioSource International). Plates were read at 450 nm on a SPECTRAmax 340PC plate reader (Molecular Devices).

    Plasma oxygen radical absorbance capacity. Antioxidant activity in protein-free plasma was determined using the ORAC assay, as previously described for a 96-well microplate reader (18). Briefly, protein was removed by centrifugation (12,000 x g for 5 min) and 200 µL of 6% m-phosphoric acid was added to an equal volume of plasma. Samples were diluted with phosphate buffer and fluorescence loss was monitored on a 96-well fluorescent microplate reader (Molecular Devices). Data are from d 1, 35, and 77 of treatment and is expressed in mmol Trolox equivalents/L of plasma.

    Plasma vitamin C analysis. Total plasma vitamin C in samples collected from d 1, 35 and 77 was determined using a modification of the dinitrophenylhydrazine (DNPH) assay (19). Plasma was combined with DNPH-thiourea-copper sulfate reagent at a ratio of 3:1, vortexed, and incubated at 37°C for 2 h. After chilling for 10 min, 1.5 mL cold 65% H₂SO₄ was added and tubes were incubated in the dark for 30 min at room temperature. Duplicate samples (270 µL) of the final reaction were transferred from each tube to duplicate wells of a 96-well flat-bottom plate. L-ascorbic acid was used to prepare a standard curve, and the absorbance was measured at 520 nm on the SPECTRAmax 340PC plate reader. Vitamin C values are expressed as µmol/L of plasma.

    Epstein-Barr virus antibody titers. The level of EBV antibody in the plasma, as an indicator of stress, was determined using an ELISA kit for EBV Viral Capsid Antigen p18 IgG antibodies (DiaSorin), according to the manufacturer's directions.

    Carotenoid analysis. Plasma samples were analyzed by Craft Technologies for carotenoids by HPLC, as previously described (20). Serum concentrations of vitamin A (retinol and retinyl palmitate) and carotenoids (lutein, zeaxanthin, -cryptoxanthin, ß-cryptoxanthin, trans lycopene, cis lycopene, -carotene, trans ß-carotene, cis ß-carotene) were measured using HPLC with absorbance detection. A small volume (150 µL) of serum/plasma was mixed with an equal volume of buffer, then mixed with ethanol containing the internal standard (tocol). The analytes were extracted from the aqueous phase into hexane. The combined hexane extracts were dried completely under vacuum, and the extract was redissolved in ethyl acetate and diluted in mobile phase. An aliquot was injected onto a C18 reversed phase column and eluted isocratically. The analytes all possessed an absorbance proportional to their concentration in solution; therefore these properties were used for quantitative analysis. The mode of detection was chosen to provide the highest sensitivity and selectivity. Carotenoids were measured by absorbance at 450 nm; retinol and retinyl esters were measured by UV absorbance at their absorption maxima of 325 nm. Chromatograms were recorded using a computer data system. Analytes were quantified by external standard quantitation using neat standards to calculate response factors based on the peak area of the analyte. The quantities of analytes were corrected for recovery post-run based upon the internal standard. Limits of detection were 3–9 nmol/L for carotenoids and retinoids. CV were <5% for retinol and -tocopherol, <7% for ß-carotene, and <11% for minor carotenoids.

    Statistical analysis. All statistics were performed using SigmaStat, version 3.11, Systat software. Demographics and population characteristics of the 2 groups were compared by t-test. Proportions in each group of those guessing the treatment to which they were assigned were statistically compared using the z-test. Regression analysis was by linear regression. Two-way repeated measures ANOVA (treatment x time) was used on most data unless otherwise stated. Post hoc analysis on results with equal variance was done using the Student-Newman-Keuls test. When equal variance failed, results were compared by the Mann-Whitney Rank Sum test. Values are means ± SEM, differences are deemed significant when P 0.05. Trends are suggested when P < 0.051–0.10.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Study attrition consisted of 1 subject due to an unrelated illness and another due to withdrawal from law school, both of which occurred within the first study week. Compliance was 87.3% ± 10.9 pills consumed in the FVJP group and 90.2% ± 9.5 in the placebo group.

The 2 groups did not differ in age, body mass index, or grade-point average at the end of the semester (Table 1). Of the individuals taking the FVJC capsule, 51.6% guessed correctly as to which capsule they took, whereas 39.3% of the placebo group guessed correctly (P = 0.493, Table 1).

The percentage of circulating -CD3⁺ T cells in the FVJC group increased 30% after 77 d, whereas treatment did not affect the percentage of ß-CD3⁺ T cells in the peripheral blood (Table 2). The percentage of -CD3⁺ T cells in the FVJC group after 77d of treatment was 30% greater than at baseline (P = 0.091) and 30% greater than in the placebo (P = 0.049).

Deproteinated plasma ORAC values significantly increased in the FVJC group over time (Table 3). Plasma ORAC values also significantly increased in the placebo group by the end of d 77, but not to the extent observed in the FVJC group. Plasma ORAC and ß-carotene values correlated (P = 0.002, r = 0.23) as did ORAC and lycopene (P = 0.026, r = 0.03) but vitamin C did not correlate with ORAC (P = 0.142, r = 0.40). At baseline, DNA damage in lymphocytes was significantly greater in the FVJC group than in the placebo group (Table 3). By d 35, DNA damage was reduced in the FVJC group to the same level as the placebo group, and was statistically lower than at baseline, with d 77 remaining the same as d 35. DNA damage in lymphocytes remained the same for all samples from the placebo group. Baseline plasma vitamin C concentrations did not differ in the 2 groups. Plasma vitamin C significantly increased in the FVJC group, but did not change in the placebo group over time (Table 3). Plasma EBV titers did not differ between groups or change over time (Table 3).

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

The FVJC group had an increase in the number of circulating -T cells compared with their baseline or with the placebo group. The subtle influence of the FVJC on these cells is appropriate because large increases in this cell type would not be expected. The number of ß-T cells did not differ in either study group.

EBV antibody titers, shown by some to be a marker for stress (16,17), did not change in either group over time. The students told us they felt stressed; however, their stress levels did not affect antibody titers. An explanation may be that people respond differently to different types of stress, e.g., stress from physical activity vs. psychological stress (21,22); thus, the type of stress experienced by this group may not affect viral titers. Lower INF- is associated with psychological stress (23); however, if this is a reflection of stress, other cytokines would be expected to change also. IL-4 decreases with stress (24) whereas IL-6 increases with stress (25). Because cytokines did not change in our subjects throughout the study, we cannot document a change in subject stress during the investigation.

The significant reduction in INF- secretion in the PBMC from FVJC consumers suggests amelioration or reorganization of immunity to a noninflamed state. INF- is a pleiotropic cytokine that is crucial for the regulation of immune responses. Lower INF- could be a result of less illness in the treatment group or potentially a response to nutrients and antioxidants in the supplement. This would have to be confirmed in another study.

The concentrations of the plasma carotenoids lutein, lycopene, and ß-carotene, were all significantly greater after the consumption of FVJC, whereas the levels of other carotenoids measured (zeaxanthin, cryptoxanthin, and -carotene) remained unchanged. Changes in immunity were shown to be influenced by carotenoids (26,27) as well as other nutrients and phytochemicals. ß-Carotene supplementation of elderly men was associated with enhanced natural killer (NK) cell cytotoxicity without altering the number of NK cells in the peripheral circulation, or secretion of INF-, INF-, or IL-12 in cultured PBMC (28). NK cells are not the only ones having cytotoxicity activity, the -T cells also have this capacity. Perhaps ß-carotene protects or supports -T cells rather than NK cells. This theory would require additional investigation.

By chance, randomization resulted in groups with different baseline lymphocyte DNA damage with the placebo group having significantly less than the FJVC group. The lower amount of DNA damage after consumption of FVJC was likely due to a variety of nutritive and nonnutritive phytochemicals, including the carotenoids (29,30) and other flavonoids and phenolic acids.

ORAC measures the quenching of the peroxyl radical–induced oxidation to measure classical chain breaking antioxidant activity (31). This suggests that the increased antioxidant capacity in FVJC consumers measured by ORAC is derived from the carotenoids, but many substances are likely to be involved in protecting against DNA strand breaks. It is not known why subjects on the placebo had slightly higher ORAC by the end of the study, however, all subjects knew they were on a dietary supplement study and possibly some individuals changed eating habits during the trial.

Plasma vitamin C concentrations in the FVJC group appeared to reach a steady state by d 35, as described in the review by Padyatty et al. (32), where vitamin C levels reach a plateau at doses of 200 mg/d and higher.

The objective of this study was to determine whether a commercially available product could potentially provide measurable health-related benefits in the study population. Most people consume only 3 servings of fruits and vegetables a day, whereas the latest guidelines are 5 servings of fruits and vegetables a day, depending on energy intake (33).

Although many phytochemicals express beneficial activities as single compounds in in vitro and animal studies, a variety of phytochemicals such as those found in plant foods, is suspected to be more effective in the prevention of disease (34,35). The formulation of the FVJC was effective in raising carotenoid levels, ascorbic acid levels, and plasma antioxidant capacity and was associated with a greater percentage of -T cells and the tendency for a reduced number of symptoms and duration of illness.

	ACKNOWLEDGMENTS

 
We thank Neal Benson and Bhavna Bhardwaj of the UF Flow Cytometry Core for assistance and guidance, Carrie NeSmith for technical assistance, and Dr. Joon-Hee Lee and Dr. Steve Talcott, for assistance with the ORAC assay. Special thanks to Gail Sassnett and Nomar Castro at the University of Florida's Levin College of Law.

	FOOTNOTES

 
¹ Supported in part by a grant to the University of Florida Institute of Food and Agricultural Sciences, Sponsored Program Agreement 04050447-C, from NSA, Inc., Collierville, TN.

² These authors contributed equally to the research and the article.

³ Abbreviations used: EBV Epstein-Barr virus; FVJC fruit and vegetable juice powder concentrate; NK natural killer; ORAC oxygen radical absorbance capacity; PBMC peripheral blood mononuclear cells; PMA phorbol 12-myristate 13-acetate.

Manuscript received 17 February 2006. Initial review completed 9 March 2006. Revision accepted 21 July 2006.

	LITERATURE CITED

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