Immunity science gets fortified

When it comes to immunomodulation, 2005 witnessed some compelling research that launched new ingredients, reinvigorated older ingredients, and, in one big study, cast aspersions on an old standby. Mark Tallon, PhD, explores

The normal functioning of our immune system is vital for optimal health and physiological function. With the 2003 outbreak of SARS, increased stress-related illnesses in the workplace, and growing pollution and antibiotic resistance, the function and maintenance of the immune system has become a hot issue on everyone's lips. This increase in public awareness of immune control has opened the door for phenomenal growth for innovative immune-boosting dietary supplements.

Of the many factors that modulate immune system function, dietary intake and its specific food components can bring about greater immune responsiveness to viral, bacterial and pathogenic challenges. The result of this enhanced immune response can be improved health, a reduced viral load and reduced disease risk.1

Although many products claim to be immune system boosters, very few have sufficient data behind them to back up these claims. In fact, assessing diet-induced changes of immune function requires targeting a large spectrum of immune system-related diseases, and subsequently the outcome and specific ranges of biomarkers. However, based on a current review of the literature, no single marker allows conclusions to be drawn about the modulation of the whole immune system, except for the clinical outcome of infection itself.1

Therefore, although this article will summarise some of the most influential developments in immuno-enhancing supplementation, be aware that combining biomarkers with high and medium suitability is currently the best approach to measure immunomodulation in human nutrition outside of clinical outcome, which is rarely assessed.

CLA and fatty acids
In recent years, the potential application of the immunomodulatory effects of polyunsaturated fatty acids (PUFAs) in a variety of inflammatory disorders has been of considerable interest to the dietary supplements industry. Dietary PUFAs and particularly those of omega-3 (n-3) and omega-6 (n-6) origin have a variety of anti-inflammatory and immune-modulating effects that may be of relevance to arteriosclerosis, myocardial infarction, stroke and sudden death.2

More recently though, conjugated linoleic acid (CLA) is one or more of eight possible twisted trans fatty acids created from linoleic acid, also known as an n-6 essential fatty acid (EFA). Its promotion as a fat-loss agent has overshadowed its use in immunity, but recent evidence is beginning to shed a light on this hazy zone. These n-3 and n-6 fatty acids appear to be the most potent of fatty acids when it comes to immunomodulation, and as such 2005 has seen some new work in these areas.

According to Doris Bell, scientist for Cognis' Tonalin brand CLA in Germany, "CLA shows tremendous promise in the area of immunity. While the majority of published clinical studies on CLA have focused on reducing body fat and maintaining lean muscle, animal studies show that CLA may play a powerful role in immunity. Initial data in humans raise hope that CLA may have effects similar to those observed in animals.

"Specifically, CLA appears to enhance cell-mediated immune defence reactions, boost immune functions especially for those who are low responders to vaccinations, and provide anti-inflammatory properties for those with asthma and probably other inflammation-based conditions," Bell said. Some studies note CLA levels may raise C-reactive protein, an inflammatory marker, while Bell notes that a study to be published next month in FASEB Journal concludes CLA intervention to have no effect on CRP levels.

Researchers from the renowned Rowett Institute, Scotland, investigated the effects of 12 weeks of CLA supplementation (3g/day: 50% CLA 9-11 and 50% CLA 10-12) on the immune system in healthy humans. The results of the study showed CLA supplementation decreased the levels of pro-inflammatory cytokines (TNF-alpha and IL-1beta) but increased the levels of the anti-inflammatory cytokine, IL-10. This shows a trend toward positive benefits of CLA on the immune system, which may beneficially affect immune function in healthy human volunteers.

Although this data is positive, more recent evidence shows little impact on human markers of immune function.4 These differences in outcome are worthy of further investigation to truly assess if CLA is an effective immunomodulator.

Researchers at the Department of Clinical Pharmacy and Pharmacology, Kagoshima University, Japan, recently investigated the influence of pre-operative (cancer surgery) immune and inflammatory response following administration of a supplement rich in arginine (12.8/l), omega-3 fatty acids (EPA = 2G DHA = 1.4g/l) and RNA (1.29/l).5 Patients in the supplements group (n = 12) received one l/day of the supplement for five days before surgery, whilst those in the control group (n = 14) received an ordinary diet without supplementation before surgery. Plasma levels of omega-3 and omega-6 fatty acids, thromboxane B(2), prostaglandin E(2), inflammatory markers, nutritional markers, cytokines and cytokine receptors were obtained five days before the operation at the starting point of supplementation in the supplements group. Samples were collected on post-operative days (PODs) including days 0, 1, 3 and 7.

After taking the supplement, significant increases in omega-3 fatty acids and rapid turnover proteins were found the day after ending supplementation (POD-0), whereas thromboxane B(2) levels and the ratio of omega-6 fatty acids to omega-3 fatty acids were significantly lower than before supplementation. On POD-0 only, inflammatory markers and cytokine receptors in the supplements group showed low levels in comparison with the control group. On POD-1 and POD-3, remarkable decreases in polymorphonuclear leukocyte-elastase and interleukin-8 in the supplements group were observed. These findings suggest that oral administration of a supplement rich in omega-3 fatty acids for five days before surgery may improve not only pre-operative nutritional status but also pre-operative and post-operative inflammatory and immune responses in patients who have cancer.

Beta-glucans are a heterogeneous group of glucose polymers found in fungi, plants and some bacteria. These fungal extracts have been known to modulate immune function for millennia, but interest over the last few decades has focused particularly on beta-glucans. The administration of purified beta-glucans has been shown to have a number of beneficial effects, including protection against infections with fungal, bacterial, viral and protozoal pathogens.6 As such, this firm foundation paved the way for beta-glucan development for use in the dietary supplements sector.

"Oat beta-glucan has long been recognised as a topical immuno-stimulant and has been extensively used as an anti-inflammatory agent in skin-care products," said Richard Potter, PhD, chief science officer of Nurture. "More recently, oat beta-glucan has been investigated orally and parenterally as a means of enhancing resistance to bacterial and parasitic infections, and this has shown considerable promise in animal models."7,8

This is exemplified by a series of animal studies at the University of South Carolina using concentrated oat beta-glucan (OatVantage brand from Nurture Inc).9,10,11,12 These studies demonstrated significantly improved morbidity, mortality and resistance to herpes simplex virus (HSV-1) with oat beta-glucan; also, lung tumour metastasis was significantly reduced.

It is believed this is generally related to the affinity of the beta-(1-3) linkage toward specific macrophage receptors. Since the same receptors occur in humans, there is potential for developing this treatment as a countermeasure against the increasing occurrence of microbial resistance to antibiotics and other widely used pharmaceuticals.

Recent work has investigated the effects of beta-glucan on immune function in weaned piglets.13 Pigs were fed a diet without or with supplemented beta-glucan (50mg/kg feed). All pigs were injected with ovalbumin (OVA) on day 14 to investigate their humoral immune response (OVA is used as a well-defined antigen bringing about well-studied immune responses).

On day 28, lymphocytes were isolated from all pigs to determine the effects of beta-glucan on cellular immunity of pigs in vitro. Lymphocytes from six pigs of each group were incubated with lipopolysaccharide (LPS). Samples were collected at 0, 3, 6, 12, 18, 24 and 48 hours after LPS addition for determination of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10).

On day 31, six pigs of each group were injected with either LPS (25 microg/kg body weight) or an equivalent amount of sterile saline. Blood samples were collected at three hours after LPS injection for analysis of IL-6, TNF-alpha and IL-10 in plasma.

The results indicate that dietary beta-glucan enhanced pig antibody response to OVA only in the first week after injection. In vitro, the increases of IL-6 and TNF-alpha in culture medium were partially dampened in pigs supplemented with beta-glucan when their lymphocytes were incubated with LPS. In vivo, dietary beta-glucan attenuated the increase of plasma IL-6 and TNF-alpha, and enhanced the increase of plasma IL-10 when pigs were challenged with LPS.

This evidence further demonstrates that beta-glucans can improve the humoral immunity of pigs and modulate cellular immunity of pigs by mitigating the elevation of pro-inflammatory cytokines and enhancing the increase of anti-inflammatory cytokines after an immunological challenge.

Lactoferrin and whey
Lactoferrin is a non-heme iron-binding glycoprotein produced during lactation and by epithelial cells at mucosal surfaces. The protein is a prominent component of the first line of host defence, and its expression is upregulated in response to inflammatory stimulation.

The results of recent pre-clinical and clinical studies demonstrating that lactoferrin acts as an inhibitor of dermal inflammatory cytokine production have been summarised.14 Lactoferrin seems to act as an anti-inflammatory protein at local sites of inflammation, including the respiratory and gastrointestinal tracts. From the looks of recent work, this seems to have been further corroborated.

Experimental evidence from previous studies supports the conclusion that orally administered lactoferrin restores the immune response in mice treated with a sub-lethal dose of cyclophosphamide, an antineoplastic agent that prevents cancerous growth.15 The aim of a study carried out by researchers at the Institute of Immunology and Experimental Therapy of the Polish Academy of Sciences was to elucidate potential benefits of lactoferrin in mice undergoing chemotherapy with Busulfan and Cyclophosphamide, followed by intravenous injection of bone marrow cells. Busulfan, like cyclophosphamide, is an antineoplastic medication.

Mice were treated orally with Busulfan (4mg/kg) for four consecutive days, followed by two daily doses of Cyclophasphamide delivered intraperitoneally at a dose of 100mg/kg and reconstituted the next day an injection of syngenetic bone marrow cells. One group of these mice was given lactoferrin in drinking water (0.5 per cent solution). After treatment, mice were immunised with ovalbumin to subsequently determine humoral immunity by evaluation of splenic antibody-forming cells.

Humoral and cellular immune responses of mice treated with chemotherapeutic agents were markedly impaired. This impairment was attenuated by oral administration of lactoferrin, with humoral immunity falling to levels that were 66-88 per cent lower than those that were untreated. Humoral immunity of lactoferrin-treated animals was equivalent to that of untreated mice within one month. Cellular immune responses were inhibited by chemotherapy treatment to a lesser degree, reaching levels that were approximately 50 per cent lower than those of untreated animals.15

In summary, this study suggests that lactoferrin may be useful in accelerating the restoration of immune responsiveness induced by chemotherapy in bone marrow transplant recipients.

The state of the science with whey protein on immune responses is growing. "There is ample evidence from human trials to demonstrate that whey, which typically contains about 50 per cent beta-lactoglobulin, increases glutathione status in white blood cells,"16,17 said nutritional and protein biochemist Robert Child, PhD, CEO of Alimentarious, a UK-based consultancy. "In immune-compromised subjects, this can translate to increased cytokine production, natural killer cell activity and lower incidence of infections.18,19 These endpoints are likely to reflect genuine immune-stimulating effects, either from beta-lactoglobulin or whey protein in its entirety."

Although whey may affect immune system function, it is unlikely the weight of this response will come from lactoferrin because it is representative of only about 1 per cent of product weight and is cost-prohibitive for wide-scale production.

There is significant interest in the use of mushrooms and/or mushroom extracts as dietary supplements based on theories that they enhance immune function and promote health. The therapeutic effects of mushrooms, such as anticancer activity, suppression of autoimmune diseases and allergy, have been associated with their immunomodulating effects.20

To some extent, select mushrooms have been shown to have stimulatory action on immune responsiveness, particularly when studied in vitro. In particular, the ability of selective mushroom extracts to modulate the differentiation capacity of CD4 (+) T cells to mature into T(H)1 and/or T(H)2 subsets will be discussed. (These cells mediate immune responses by controlling factors such as the inflammatory response.)21

But despite their widespread use for potential health benefits, there is a surprising paucity of epidemiological and experimental studies that address the biologic activities and safety of mushrooms after oral administration to animals or humans.

However, researchers from The Hong Kong Polytechnic University investigated the toxicity of effects of four weeks Lingzhi (Ganoderma lucidum) supplementation on a range of liver and renal toxicity markers.22 Fasting blood and urine from 18 healthy adults were collected before and after four weeks supplementation with a commercially available encapsulated Lingzhi preparation (1.44g/day Lingzhi, equivalent to 13.2g/day fresh mushroom) or placebo. No significant change in any of the variables was found. Theses results showed no evidence of liver, renal or DNA toxicity with Lingzhi intake. This study shows that this form of mushroom use over the short term is safe.

Data from the same group investigated the in vitro antioxidant capacity of 10 days on a slightly lower dose of Lingzhi on biomarkers of antioxidant status, coronary heart disease (CHD) risk and DNA damage.23 In this double-blind, placebo-controlled, cross-over trial, blood and urine samples were collected from healthy volunteers at 0 (fasting) and 45, 90, 135 and 180 minutes post-ingestion of 1.1g Lingzhi. Repeat fasting samples were collected after 10 days' supplementation with 0.72g/day Lingzhi. The acute response (up to three hours) was also investigated with a larger dose (3.3g) of Lingzhi in a sub group of seven subjects.23

Results showed that the total antioxidant capacity (as the FRAP value) of an aqueous suspension of Lingzhi was 360micromol/g. Ingestion of Lingzhi caused a significant post-ingestion increase in plasma antioxidant capacity, with peak response at 90 minutes. Average increase of 29+/-11 per cent in urine antioxidant capacity was seen within three hours of ingestion.

After 10 days' supplementation with 0.72g/day Lingzhi, fasting plasma lipid standardised alpha-tocopherol concentration and urine antioxidant capacity increased. Fasting plasma ascorbic acid and total alpha-tocopherol concentrations and erythrocyte SOD and GPx activities increased slightly but nonsignificantly with supplementation. Plasma lipids and uric acid tended to decrease, but changes were not statistically significant. No deleterious effects on measured variables were seen.

Results indicate that Lingzhi intake causes an acute increase in plasma antioxidant capacity.23 The pattern of biomarker response after supplementation indicated possible benefit in terms of antioxidant status and CHD risk, but further study is needed to elucidate the nature and longer-term effects of the absorbable antioxidants from Lingzhi.

The future
Like immune-compromising disease states, the immune support and condition-specific prevention arenas are poised for explosive growth and innovative formulations. There are a many other active nutrients demonstrated in recent studies to act as potent immunomodulators based on current research, including vitamin E,24 nucleotides,25 flavonoids26 and glutamine.27

However, some fundamental flaws should be considered when looking at all of these studies. One example of why caution must be taken can be seen with the use of whey extracts.28 It has been reported that the use of beta-lacatoglobulin preparations to stimulate immune cells in vitro can be caused by endotoxin contamination.28 Therefore, the immune responses seen with beta-lactoglobulin could be reported as a positive benefit of beta-lactoglobulin, when in reality it is because of supplement contamination as a result of poor GMPs.

Similar reports have shown the presence of bacterial and fungal contamination of many other bioactives.29 This gives more weight to the importance of raw ingredient selection and screening for the general public, and researchers investigating the beneficial influences of functional foods/dietary supplements on immune system responses.

Mark J Tallon, PhD, is chief science officer of OxygeniX, a London-based consultancy firm specialising in claims substantiation, product development and technical writing.
Dr Tallon is also co-founder of Cr-Technologies, a raw-ingredients supplier.

A synbiotic combination: has their time finally come?

Probiotics and prebiotics stimulate health-promoting indigenous flora to affect pathogen colonisation and disease expression.1 Probiotics are live flora given in oral quantities that allow for colonisation of the colon. Probiotics activate the mucosal immune system and prevent pathogen colonisation and translocation by strengthening the mucosal barrier, interfering with pathogen colonization and, in some instances, producing secretary antibacterial substances.2

These nondigestible carbohydrates have been shown to act upon the gut-associated lymphoid tissue, which is an accumulation of lymphocytes or lymph follicles scattered beneath the epithelium throughout the gastrointestinal tract. Furthermore, a series of pattern-recognition receptors — toll-like receptors on gut lymphoid and epithelial cells that interact with bacterial molecular patterns (eg endotoxin, flagellin, etc) — help modulate intestinal innate immunity and an appropriate adaptive immune response.3

The combination of prebiotics and probiotics has a vast vault of efficacy-supporting data. However, as the market becomes product-saturated, innovative formulations must be devised to stand out in this crowded market space. But what is the evidence behind the new generation of combination products? In a recent randomised, double-blind, placebo-controlled trial, researchers have attempted to answer such questions.4

In this study, subjects were supplemented with probiotic bacteria plus vitamins and minerals (probiotic group) for three months.4 The duration, frequency and severity of symptoms of the common cold infection as well as cellular immune parameters were assessed in 477 healthy men and women (aged 36 +/- 13 years) who had not been vaccinated against influenza. Participants were randomly assigned to a group who received daily the probiotic supplement or a placebo, for three (n=239) or five-and-a-half months (n=238).

The incidence of virally induced respiratory tract infections was 13.6 per cent lower in the probiotic group vs the placebo group. During episodes of respiratory tract infection, subjects recorded common cold and influenza-like symptoms daily with all symptoms reduced in the probiotic group.4 They found a relative reduction of 19 per cent in the total symptom score, 25 per cent in influenza symptoms and 54 per cent in the number of days with fever. Leukocytes; lymphocytes, in particular T-lymphocytes including CD4+ and CD8+ cells; as well as monocytes, were significantly increased in the probiotic group during the first 14 days of supplementation vs placebo.4

These data indicate that the intake of a dietary supplement containing probiotic bacteria plus vitamins and minerals during a period of at least three months may reduce the incidence and severity of symptoms in common cold infections in otherwise healthy adults.

1. Chen CC, Walker, WA. Probiotics and prebiotics: Role in clinical disease states. Adv Pediatr 2005; 52:77-113.
2. Watzl B, et al. Inulin, oligofructose and immunomodulation. Br J Nutr 2005; 93 Suppl 1:S49-55.
3. Johansson-Lindbom B, et al. Selective generation of gut tropic T cells in gut-associated lymphoid tissues (GALT): Requirement for GALT dendritic cells and adjuvant. J Exp Med 2003; 198(6):963?9.
4. Winkler P, et al. Effect of a dietary supplement containing probiotic bacteria plus vitamins and minerals on common cold infections and cellular immune parameters. Int J Clin Pharmacol Ther 2005; 43(7):318-26.

Body of evidence holds echinacea in good standing

The latter-day lack of consumer confidence in the effectiveness in echinacea could come from a recent study presented in the New England Journal of Medicine.1 Researchers from Virginia assessed the influence of E. angustifolia supplementation on rhinovirus infection. The authors assessed 437 subjects divided into three groups to receive one of three different preparations of E. angustifolia seven days prior to viral challenge.

The study, although creating wide spread acclaim amongst the broadsheets, was fundamentally flawed in its design. The main flaw was that the dose given in the study was equal to 750mg per day. The problem with this is that previously published data shows a dose-dependent effect of echinacea.

In 1992, a study assessing the influence of either 1,800mg or 900mg dose of E purpurea on respiratory tract infection.2 Patients receiving the high dose experienced significant relief of symptoms, yet those on the lower dose were not significantly different from those on placebo. In fact, most herbal practitioners recommend doses of up to and equivalent of 2,500mg. So what of recent work that further confirms the positive effects of echinacea on our immune systems?

One recent study investigated the effect of echinacea tablets on the expression of leucocyte heat shock protein 70 (hsp70), erythrocyte haemolysis, plasma antioxidant status, serum chemistry, hematological values and plasma alkylamide concentrations.3 Following 15 days of consuming two commercially blended echinacea tablets, supplementation enhanced leucocyte hsp70 expression and white cell counts, and prevented erythrocyte haemolysis after a mild heat shock. This pilot study identifies echinacea's immunomodulation via altered expression of hsp70 and increased WCC.

Moving deeper in our understanding of echinacea, recent evidence has measured gene expression responses over a 12-day period following 1,518mg/day for two days and 506mg on the third day.4 This study is one of the first to assess the genetic influence of echinacea and identified specific anti-inflammatory response and gene regulation, which was consistent with echinacea's ability to reduce the duration and intensity of cold and flu symptoms.

1. Turner RB, et al. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med 2005; 353(4):341-8.
2. Braunig B, Dorn M, et al. Echinacea purpurea radix for strengthening the immune response in flu-like infections. Z Phytother 1992; 13:7-13.
3. Randolph RK, Gleenbeck K, et al. Regulation of human immune gene expression as influenced by a commercial blended Echinacea product: Preliminary studies. Exp Biol Med 2003; 1051-6.
4. Agnew LL, et al. Echinacea intake induces an immune response through altered expression of leucocyte hsp70, increased white cell counts and improved erythrocyte antioxidant defences. J Clin Pharm Ther 2005; 30(4):363-9.

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2. Calder PC. Polyunsaturated fatty acids and inflammation. Biochem Soc Trans 2005; 33:423-7.
3. Song HJ, et al. Effect of CLA supplementation on immune function in young healthy volunteers. Eur J Clin Nutr 2005; 59(4):508-17.
4. Nugent AP, et al. The effects of conjugated linoleic acid supplementation on immune function in healthy volunteers. Eur J Clin Nutr 2005; 59(6):742-50.
5. Nakamura K, Kariyazono H, et al. Influence of preoperative administration of omega-3 fatty acid-enriched supplement on inflammatory and immune responses in patients undergoing major surgery for cancer. Nutrition. 2005; 21(6): 639 - 649.
6. Brown GD, Gordon S. Immune recognition of fungal beta-glucans. Cell Microbiol 2005; 7(4):471?9.
7. Yun C-H, et al. Beta-glucan, extracted from oat, enhances disease resistance against bacterial and parasitic infections. Immun Med Microbiol 2003; 35:67-75.
8. Estrada A, et al. Immunomodulatory activities of oat beta-glucan in vitro and in vivo. Microbiol Immunol 1997; 41:991-8.
9. Davis JM, et al. Effects of oat beta-glucan on innate immunity and infection after exercise stress. Med Sci Sports Exerc 2004; 36:1321-7.
10. Murphy EA, et al. Role of macrophages on the benefits of ObG on susceptibility to infection following exercise stress. Abstract (ACSM Annual conference 2005).
11. Davis JM, et al. Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection. Am J Physiol Regul Integr Comp Physiol 2004; 286:R366-R372.
12. Murphy EA, et al. Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity. J Appl Physiol 2004; 97:955?9.
13. Li J, et al. Effects of beta-glucan extracted from Saccharomyces cerevisiae on humoral and cellular immunity in weaned piglets. Arch Anim Nutr 2005; 59(5):303-12.
14. Legrand D, et al. Lactoferrin: a modulator of immune and inflammatory responses. Cell Mol Life Sci 2005; 62(22):2549-59.
15. Artym J, et al. Lactoferrin accelerates reconstitution of the humoral and cellular immune response during chemotherapy-induced Immunosuppression and bone marrow transplant in mice. Stem Cells Dev 2005; 14(5):548-55.
16. Lands LC, et al. Effects of supplementation with a cysteine donor on muscular performance. J Appl Physiol 1999; 87(4):1381-5.
17. Middleton N, et al. Whole blood and mononuclear cell glutathione response to dietary whey protein supplementation in sedentary and trained male human subjects. Int J Food Sci Nutr 2004; 55(2):131-41.
18. Moreno YF, et al. Features of whey protein concentrate supplementation in children with rapidly progressive HIV infection. J Trop Pediatr 2005; 13 (in press).
19. Watanabe A, et al. Nutritional therapy of chronic hepatitis by whey protein (non-heated). J Med 2000; 31(5-6):283-302.
20. Kuo MC, et al. Ganoderma lucidum mycelia enhance innate immunity by activating NF-kappa B. J Ethnopharmacol 2005 (in press).
21. Lull C, et al. Antiinflammatory and immunomodulating properties of fungal metabolites. Mediators inflamm 2005; 2:63-80.
22. Wachtel-Galor S, et al. Ganoderma lucidum ('Lingzhi'), a Chinese medicinal mushroom: biomarker responses in a controlled human supplementation study. Br J Nutr 2004; 91(2):171-3.
23. Wachtel-Galor S, et al. Ganoderma lucidum ('Lingzhi'); acute and short-term biomarker response to supplementation. Int J Food Sci Nutr 2004; 55(1):75-83.
24. Meydani SN, et al. Vitamin E and immune response in the aged: molecular mechanisms and clinical implications. Immunol Rev 2005; 205:269-84.
25. Hawkes JS, Gibson RA, et al. Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial. Eur J Clin Nutr 2005 (in press).
26. Ramiro E, et al. Effect of Theobroma cacao flavonoids on immune activation of a lymphoid cell line. Br J Nutr 2005; 93(6):859-66.
27. Yeh CL, et al. Dietary glutamine supplementation modulates Th1/Th2 cytokine and interleukin-6 expressions in septic mice. Cytokine. 2005; 31(5):329-34.
28. Brix S, et al. Immunostimulatory potential of beta-lactoglobulin preparations: effects caused by endotoxin contamination. J Allergy Clin Immunol 2003; 112(6):1216-22.
29. Raman P, et al. Evaluation of metal and microbial contamination in botanical supplements. J Agric Food Chem 2004; 29(26):7822-7.

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