Nutritional Impact on Immune Function

Strength. Protection. Defense. Perseverance. These are the words one thinks of when considering immunity. We all try to keep from getting sick by taking precautions like washing our hands, covering our mouths and, especially, maintaining a healthy diet. Providing the body the right nutrients helps it work 24/7/365 to ward of invaders, called pathogens, be they viral, bacterial, fungal or other biological evil agent.

The immune system is a multilayer masterpiece of barriersmucosal surfaces, skin and other membranesand chemical defenders that work together to confront and banish pathogens. Their quest is for balance, as some components promote actions, such as inflammation and apoptosis (cell death), while others counter those actions when the goal is achieved, keeping the system in check. A hyper-stimulated system can lead to autoimmune problems, and a suppressed system can lead to further infection; both can lead to degeneration.

The key mobile components of this system are white blood cells called leukocytes. These include lymphocytes, which include B cells, T cells (T-helper and cytotoxic T cells) and natural killer (NK) cells; monocytes, which become either macrophages (consume pathogens) or dendritic cells (activate T lymphocytes); neutrophils (hunt bacteria and fungi); eosinophils, which target larger parasites; and basophils, which are responsible for releasing histamine.

Untriggered B cells circulate through the lymph system until they are activated in the thymus or by a T cell to produce antibodies (i.e., immunoglobulins), which each specialize in a specific antigen. There are five classes of immunoglobulins: immunoglobulin G (IgG), IgA, IgM, IgD and IgE.

T cells form the foundation of cell-mediated immunity, responding to self-cells that have changed due to a virus or a cellular mutation. Among the various T cell types, cytotoxic T cells cause cell death and attract macrophages for continued consumption of the foreign matter. Helper T cells, known as CD4 or CD8 cells, stimulate the activity of cytotoxic T cells. The two subclasses of CD4 cells are Th1 and Th2, each of which releases interleukins to trigger particular immune functions. Th1 responses activate macrophages to kill pathogens, create inflammation, stimulate antibody production and secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). And, Th2 responses feature high levels of antibody production, including secretion of certain antibodies and production of IL-4, IL-5, IL-10 and IL-30.

In addition to these worker cells, the immune system involves two fluid-like components. Complement is a mixture of proteins and proteases that can trigger production of cytokines that help kill foreign cells in membranes. Lymph is a plasma-like interstitial (between body cells) fluid that contains nutrients and white blood cells, and travels to and from lymph nodes, which are where lymphocytes meet antigens (foreign substances) caught up in the nodes.

The intricate science on immune function is reflected in the recent research on various nutrients and nutraceutical ingredients and their effects on various factors of immune modulation. Immune function is one of the hottest health research categories, with new results coming out every month. What follows is an overview of some such results spanning a variety of ingredients, from micronutrients and plant-based compounds to mothers milk and live cultures.

The first stop in most dietary interventions is basic nutrients. Vitamins and minerals certainly have shown an impact on mechanisms of immune response. Most people are familiar with vitamin C supplements for cold and flu seasonC has been shown to help maintain cellular integrity and improves NK and lymphocyte activity¹but a recent study showed how vitamin D might play a role in survivability during a particularly difficult immune challenge: lymphoma.

Researchers from the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE), which is funded by the National Cancer Institute (NCI), studied 374 newly diagnosed diffuse large B-cell lymphoma patients, finding half were deficient in vitamin D, based on the widely used clinical value of less than 25 mg/mL total serum 25(OH)D.² Further, after adjusting for other variables, researchers discovered those with deficient D levels were 1.5-times more likely to experience progression of the disease and twice as likely to die from it than did patients with higher D levels. In the end, lead investigator, Matthew Drake, M.D., Ph.D., an endocrinologist at Mayo Clinic, Rochester, MN, suggested vitamin D supplementation could potentially be a viable treatment option for this and other cancers, pending further investigation.

In other areas of immune health, vitamin D appears to affect signaling within macrophages and keratinocytes in the epidermis, enhancing their responsiveness to barrier defense.³ The other letter nutrients have important roles in immune response. Vitamin A, and its active metabolite retinoid acid, can influence adaptive immunity by increasing antibody response and regulating T/B cell populations and cellular differentiation.⁴ And vitamin E affects cytokine production, thereby impacting inflammatory response, especially in the elderly.⁵ In 2009, scientists at Jean Mayer USDA Human Nutrition Research Center, Boston, observed differences in vitamin Es immune actions are influenced by genes.⁶

On minerals, zinc functions as an intracellular signal molecule for immune cells.⁷ Similar to deficiency of vitamin D, a lack of sufficient zinc in the body has been linked to increased production of pro-inflammatory cytokines and oxidative stress.⁸ On the flip side, normal plasma zinc concentrations correlate to decreased risk of pneumonia.⁹ Likewise, zinc supplementation (as zinc gluconate) appears to lessen the chances of infection.¹⁰

Selenium rounds out the recent mineral research, with deficiency of selenium, especially selenoproteins, having been associated with diminished macrophage activities, according to a 2009 NCI study.¹1 Chinese Academy of Sciences, Beijing, researchers confirmed the negative effect low selenium levels can have on innate immunity, showing selenium-deficient animals were more not only more susceptible to bacterial infection (Listeria monocytogenes), but also suffered a decreased response to the infection.¹²

When one looks at the world and nature and thinks what exemplifies strength, self-protection, defense and survival, the plant world might not be immediately inspiring, but plants grow in some mighty challenging environments. It makes sense, then, the compounds in a plant that help defend it from the elements (air, etc.) would be similarly beneficial in the human body.

 The market for immune products, namely cold and flu season items, is no stranger to herbs such as Echinacea, elderberry and garlic, which deliver antibacterial, antiviral and/or other immune boosting properties. However, positive recent immune research results have been turned in by some lesser-known plants whose compounds have very scientific monikers.

Astragalus membranaceous is a Chinese adaptogenic herb credited with immunomodulating and restorative effects in vitro and in vivo, based on its enhancement of macrophage phagocytic activity and lymphocyte response in cases of immunosuppression.¹³ Astragalus paired with goldenseal (Hydrastis canadenisis) has modulated the response of stimulated macrophages. Alone, astragalus affects production of TNF-alpha.¹⁴

From India comes an infection fighter called Andrographis paniculata. In 2009, scientists from India sought to shed some light on this herbs immunomodulatory effects, finding andrographilides from this plant appear to normalize immune responses altered during antigen interaction, as well as reverse immunosuppression.¹⁵ Chinese researchers also added to the knowledge base on andrographis, reporting the herb, in conjunction with two other Traditional Chinese Medicine (TCM) botanicals, inhibited inflammatory compounds such as nitric oxide (NO) and prostaglandin2 (PE2) by suppressing NFkappaB,¹⁶ a regulator of immune response to infectionsNFkappaB factors in inflammation, autoimmune diseases and cancer. A few years prior, Indian scientists found both andrographis extract and isolated andrographilide enhanced NK cell activity and elevated production of interleukin-2 (IL2) and interferon-gamma in both healthy and cancerous animal subjects, in addition to improving antibody-dependent complement-mediated cytotoxicity.¹⁷

Another botanical used traditionally in India, curcumin, is well-recognized as anti-inflammatory, and it has shown great promise as a destroyer of cancer cells, using its powers of apoptosis. This has proved useful against Alzheimers disease (AD), as well, according to 2009 UCLA research showing curcuminoids combined with vitamin D3 improve innate immunity in AD patients and stimulate type I macrophages to clear amyloid plaques that cause such neuronal problems in the disease.¹⁸ 

However, curcumins ability to clear out cancer cells might not be just due to apoptosis. Irish researchers reported in 2009 curcumin started killing cancer cells within 24 hours of administration in laboratory tests, and when they negated curcumins apoptosis ability, the botanical compound still killed cancer cells at the same rate.¹⁹ In the same year, Korean lab tests showed curcumin applied to dendritic cells could down-regulate a key enzyme in T-cell suppression-mediated immune tolerance to tumors.²⁰ They suggested this mechanism could be exploited therapeutically in the control of cancers.

Asia has its own exotic immune superstar in spirulina, an algae plant found to increase macrophage phagocytic activity, stimulate cytokine and antibody production, and activate T, B and NK cells.²¹ A 2004 Japanese study of spirulina compound phycocyanins effect on mucosal systemic immune responses and allergic inflammation in mice revealed the spirulina biliprotein enhanced secretary IgA antibody response in mucosal immunity and suppressed allergic IgE antibody response in allergic inflammation.²² Then in 2008, a Korean study reported spirulina supplementation in men resulted in a significant rise in plasma interleukin-2 (IL-2) concentration, coupled with a significant reduction in IL-6 concentration.²³

This immunomodulation in allergic inflammation was explored by University of California, Davis, researchers, who gave 1,000 mg/d or 2,000 mg/d of spirulina (from Earthrise Nutritionals) to patients with allergic rhinitis and assessed cytokine production during the 12-week trial period.²⁴ While the intervention was ineffective at modulating the Th1 cytokines, it did result in significantly lower IL-4 levels.

Another green food product, a specialty blend of edible plant extracts including barley leaves, wheat grass, chlorella and kelp (as Kyo-green, from Wakunaga) was shown, as a blend, to modulate macrophage activity better than the individual extracts tested alone, suggesting synergistic properties.²⁵

Wakunaga also generated positive immune research results on its aged garlic extract (AGE) Kyolic®, which can increase the number of NK cells and their activity among patients with inoperable cancers and patients with AIDS²⁶ and stimulate the proliferation of splenocytes and cytokine release, as well as enhance macrophage activity.²7 Further, chronic administration of AGE may help improve age-related immune response deterioration.²⁸

Pomegranate extract is a more recently popular botanical supplement whose anti-inflammatory mechanisms are showing early sign of benefit to immune events. University of Mississippi researchers attributed antioxidant, antimalarial and antimicrobial actions to tannin-rich fractions, ellagitannins and phenolic acids from pomegranate extract.²⁹ A 2007 review by University of Massachusetts, Worcester, scientists noted pomegranate juice has shown an ability to inactivate HIV, influenza, herpes viruses and poxviruses, as well as genetically diverse strains of influenza including H5N1 (avian flu).³⁰ In 2008, Korean research focused on pomegranates inhibition of the activation of the nuclear factor of activated T cells (NFAT), concluding the supplement could help suppress autoimmune activities.³¹ Most recently, a 2009 report out of University of South Carolina, Columbia, detailed how pomegranate extract significantly decreased gene expression and production of IL-6 and IL-8 in a human basophil line, concluding the polyphenol-rich supplement may have therapeutic benefit in the treatment of inflammatory diseases by suppressing mast cells/basophils activation.³² Another 2009 study upheld the infection-fighting prowess of pomegranate, detailing how pomegranate rinds combined with metal salts were the most effective formula for treating MRSA (Methicillin-Resistant Staphylococcus aureus), while other common hospital infections were best treated with the rinds, salts and vitamin C.³³

One class of compounds found in several botanicals is polysaccharides, insoluble carbohydrates. In the immunopopular Echinacea plant, arabinogalactans are the compound considered responsible for the herbs ability to stimulate macrophage activity and increase interferon, tumor necrosis factor (TNF) and IL-1 production. Extracts of E. purpurea and E. angustifolia combined with larch arabinogalactan (LAG)extracted from Larix occidentalisincreased production of factor P, a regulator of complement and an indicator of immune system stimulation.³⁴

LAG is a rich source of polysaccharides and dietary fiber, which can stimulate NK cell cytotoxicity.³⁵ In vivo research conducted at McGill University, Montreal, found LAG induced a range of cytokines and impact monocyte production.³⁶ A 2009 study investigated the ability of LAG (as ResistAid®, from Lonza) to selectively enhance antibody response to a pneumonia vaccine, a standard way to test nutraceuticals and immune functionnot a means to show treatment of pneumonia.³⁷ Results of the 72-day trial showed the LAG-based ingredient positively modulated immune function by increasing the antibody response in healthy volunteers, without increasing the nonspecific innate immune response. Specifically, IgG response was higher in the LAG group, which did not affect salivary IgA, white blood cell count, inflammatory cytokines or complement.

The traditional Indian botanical Tinospora cordifolia is another source of arabinogalactan polysaccharides, and has been used traditionally as an adaptogen. Lab tests on an extract from the stem of the plant show modulation of cytokines and NO levels, thus protecting macrophages from inflammatory challenges.³⁸ A specialized extract of T. cordifolia (as Tinofend®, from Verdure) was tested for eight weeks in allergic rhinitis sufferers, leading to significant decreases in symptoms of allergic rhinitis, with decreased neutrophil count in nasal smear.³⁹

Mighty Mushrooms

A good source of a particular type of polysaccharides, beta glucans, is medicinal mushrooms. Gaining name recognition here in the West is maitake (Grifola frondosa), which contains beta 1,3/1,6 glucans and can strongly trigger cytokine activity and up-regulate certain neutrophils in a dose-dependent manner.⁴⁰ Maitake (as D-Fraction®, from Mushroom Wisdom) may activate immune cells, macrophages dendritic cells and T cells, in addition to enhancing the cytotoxicity of NK cells.^41,42,43

Another recognizable mushroom, reishi (Ganoderma lucidum) modulates T-cell activation by acting directly on monocytes.⁴⁴ Its polysaccharides have been credited, by various researchers, with promoting splenic B cell activation and antibody secretion,⁴⁵ specifically stimulating TNF-alpha and IL-6 production and IFN-gamma release.^46,47

Coriolus versicolor is home to a special compound, protein-bound polysaccharide-K (PSK), which has both cellular and humoral immunomodulatory effects, including sparking IgM production and B cell activity, while also inducing antibody production.⁴⁸ This mushroom may also activate CD4+ T cell response in the lymph nodes and modulate T cell receptor induced IL-2 production.⁴⁹

University of Oslo, Norway, researchers noted the Asian medicinal mushroom Agaricus blazeii Murill has strong immunomodulating properties,⁵⁰ which other studies have shown includes increasing IgG levels and kindling T cell production in the spleen, as well as elevating phagocytic capability and the bodys resistance to bacterial infection.^50,51 Blazeii has also increased NK cell activity when given to cancer patients, who subsequently experienced fewer chemotherapy side effects.⁵²

One well-studied, polysaccharide-rich mushroom-based ingredient is the proprietary Active Hexose Correlated Compound (AHCC®, manufactured by Amino Up Chemical Co., U.S. distribution by Maypro Industries), derived from the mycelia of select basidiocymetes. Animal trials demonstrated AHCC can regulate adaptive and innate immune response by augmenting the bodys tumor oversight and increasing its response rate to pathogenic infection.^53,54 A Drexel University, Philadelphia, review summed AHCCs other actions, including general immune modulation and increasing survival in response to acute infection.⁵⁵ More recently, 2009 research out of Drexel concluded low-dose AHCC supplementation improves immune response to influenza infection, despite having no effect on total NK cell cytotoxicity.⁵⁶ And a 2009 animal trial out of Colorado State University, Ft. Collins, showed oral administration of AHCC increased resistance to West Nile Encephelitis.⁵⁷

Outside of the mushroom aura, the yeast Saccharomyces cerevisiae has hit the market as an apolysaccharide-rich source. A proprietary 1,3/1,6 gluco polysaccharide derived from the cell walls of the yeast (as Wellmune WGP®, from Biothera) has been tested for reduced incidence of upper respiratory infections (URIs) in populations prone to experiencing stress-related immune suppression. In one trial, firefighters taking Wellmune or placebo for 12 days (followed by a three-day washout period and another 14-day treatment period) were considerably less likely to develop URIs.⁵⁸ Similarly, of 150 subjects with high-lifestyle stress, who were randomized to receive placebo, 250 mg/d or 500 mg/d of Wellmune WGP for four weeks, fewer subjects on active treatment had any type of URI symptoms.⁵9 In a similar design, Wellmune significantly reduced the incidence of upper respiratory infection in marathon runners.⁶⁰ Then, healthy adults receiving 250 mg/d of Wellmune WGP or placebo for 90 days had less severe colds and shorter duration than those taking placebo. In 2009, published research results reported Wellmune supplementation in adults reduced the incidence of fever and eliminated the need for study subjects to miss work or school due to colds.⁶¹

According to new research from Biothera presented recently at the National Cancer Institutes Frontiers in Basic Immunology 2009, slight structural differences between seemingly identical beta 1,3/1,6 glucans from different sources can greatly impact immune benefits. In the study, beta 1,3/1,6 glucans from three separate sources with similar primary structures were combined with a monoclonal antibody in a lymphoma model. Results showed the survival rate of animals treated with Biotheras Imprime PGG was more than double that of subjects receiving one of the other sourced glucans.

EpiCor®, from Embria Health Sciences, is another Saccharomyces cerevisiae-based ingredient, this one featuring a high-metabolite immunogen derived via fermentation. A pair of 2007 trials examining EpiCor (500 mg) and a placebo on cold and flu incidence and symptoms in flu-vaccinated and non-flu-vaccinated adults found active intervention significantly reduced the incidence of URIs, as well as the duration of symptoms in subjects who did get URIs. Subsequent research confirmed 500 mg/d of EpiCor can also increase IgA and decrease IgE levels. This same dose of EpiCor was studied by NIS Labs, which found those taking EpiCor increased levels of hematocrit and IgA, along with decreases in serum IgE and increases in IL-10. Most recently, a 2009-published study 500 mg/d EpiCor for 12 weeks in healthy adults during high-pollen season led to less severe allergic rhinitis symptoms including nasal congestion; IgA levels were also heightened in the Eipcor group.⁶²

A Mothers Gift

One of the greatest gifts a mother can give her offspring is the gift of immunity. For cows, this is called bovine colostrum, and it is a hot ingredient in the immune health market. Test tube research suggested bovine colostrum supplementation could modulate cytokine production and trigger the release of IFN-gamma, IL-10 and IL-2.⁶³ An early clinical trial showed colostrum in healthy adults encouraged production of IL-12, and showed a antigenic-dependent impact on IFN-gamma productionenhanced IFN-gamma in response to weak stimulation and inhibited IFN-gamma after strong stimulation.⁶⁴ On endurance-mediated immune suppression, colostrum supplementation by cyclists inhibited the usual post-exercise decrease in cytotoxic T cells and sIgG concentrations; it also appeared to reduce incidence of URIs.⁶⁵

A 2009 Harvard Medical School research review noted oligosaccharides and other glycans in human milk represent an innate immune system that can be transferred from mother to child to protect against enteric and other pathogens.⁶⁶ They added colostrum may be a useful therapeutic agent to inhibit disease by mucosal pathogens in many species.

One related ingredient (AiE10®, from Dietary Ingredient Solutions) combines defensin, granulysin, transfer factors and mini-cytokines derived from colostrum via a proprietary infusion technology. A 2006-published comparative study involving AiE10, colostrum, maitake, arabinogalactan, lactoferrin and astragalus found immune boosting across all the ingredients, but Ai/E10 also had a strong, reliable capability to increase immune surveillance and transfer immunological information among cell groups.⁶⁷ Unpublished research also demonstrates AiE10 can help ward off MRSA infection.

A category of ingredients often found in milk-based products are beginning to make some positive noise in the immune health research segment, based also on innate immunity. Probiotics are friendly bacteria that crowd out harmful bacteria from receptor sites, especially in the stomach, but also in the oral cavity and other parts of the body including mucosal membranes.

A few trials surfaced in 2009 that confirmed these benefits. A combination of Lactobacillus acidophilus NCFM® and Bifidobacterium lactis Bi-07 (as HOWARU® Protect, from Danisco) administered to children decreased their fever incidence by 72.7 percent, while L. acidophilus alone reduced incidence by 53 percent.⁶⁸ Also, coughing decreased by 41.4 percent, and 62.1 percent of runny noses were lessened by 28.2 percent for the combination and 58.5 percent for the single strain. The probiotics also reduced the duration and severity of cold and flu symptoms.

Children starred in another probiotic/immune trial, as a double blind, randomized, controlled, multicenter study using a synbiotic combination of Lactobacillus Rosell-52, Bifidocterium Rosell-71, Bifidobacterium Rosell-33 and fructooligosaccharides prebiotic (as ProbioKid®, from Institut Rosell-Lallemand) was presented at the 5th Probiotics, Prebiotics & New Foods Meeting held in Rome, September 2009. According to the presentation, ProbioKid helped reduce the incidence of infectious episodes in school-aged children during the winter period. Also presented were results from testing probiotic formulas on immune gene expression by intestinal epithelial cells and immune cells (macrophages). ProbioKid and a single-strain product (L. Plantarum 299v) demonstrated such an effect on gene expression, and triggered distinct gene response profiles in both cell types. Specifically, ProbioKid down-regulated the expression of IL8, an inflammatory marker.

Most recently, a University of Colorado, Denver, research report noted an eight-strain probiotic formulation administered to mice bred to have a specific inflammatory bowel disease inhibited intestinal inflammation by stimulating epithelial innate immune responsesincreased production of epithelial-derived TNF- and restoration of epithelial barrier function in vivoin five of the 11 mice studied.⁶⁹

Also operating on the mucosal level to promote immune balance, a marine-based ingredient (Peptibal®, from innovActiv) promotes the synthesis of antibodies specialized in mucosal defense, helping to tighten the junction between the cells to solidify the thin barrier and providing a more efficient immune response. In 2009, results from a randomized, double blind, placebo-controlled human clinical trial conducted by Laval University, Quebec City, showed Peptibal produced a statistically significant increase in IgA productionimportant for passive immunityin men by 17.4 percent over placebo after 28 days of taking 300 mg/d.⁷⁰

Immune health is certainly a hot category, and given the continuous viral and bacterial epidemics society continues to face, the opportunity for scientifically backed natural ingredients to make an impact on the market will persist.

References on the next page...

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