Immune Function

References

The principal role of the immune system is to defend the body against disease. Much like the military of a large nation, the complex association of special tissues, organs, cells, and chemicals comprising the immune system patrols all fronts of the body—from mucous membranes to organs to blood—in search of hostile foreign invaders to attack and destroy.

There are two tiers of immune response: innate and adaptive. Innate immunity, the body’s first level of security against infection, is present from birth and consists of barrier systems located at basic ports of entry such as the skin and mucus membranes, and throughout the gastrointestinal (GI) tract, where the majority of infectious agents enter the body. Secretions produced in these areas contain defense cells such as macrophages, neutrophils and immunoglobulins, which destroy unwanted germs before they can infiltrate more vulnerable areas.

The reactions of innate immunity trigger adaptive immunity. Adaptive immunity, the second level of protection against disease, is an acquired defense mechanism attained from immunization or exposure to infection and refers to the targeting of specific antigens by antibody-producing lymphocytes.

Lymphocytes, specialized white blood cells with key roles in immune function, include B cells and T cells. B cells, derivates of stem cells produced in bone marrow, circulate through the lymph system in search of antigens. Each B cell is programmed to make one antigen-specific antibody, which is produced upon encountering its triggering antigen; the size of the lymphocyte population (1 trillion cells) suggests there may be B cells available to destroy any type of antigen. T cells, meanwhile, also created in bone marrow but activated in the thymus, work in concert with B cells to fight infection. When a pathogenic invader is detected, its proteins are broken down into short peptide chains and displayed on the surfaces of macrophages and B cells. When T cells detect this display, they stimulate B cells to begin antibody production.

Another class of leukocytes involved in innate immunity—natural killer (NK) cells—detects and destroys infected and cancerous cells by attaching to targets and releasing lethal bursts of chemicals that penetrate the cell wall. When the cell wall is breached, fluids leak across either side of the membrane and the target eventually explodes.

The antioxidant vitamin C promotes healthy immune function in a number of ways. It supports the activities of white blood cells, including production of antibodies and interferon (a protein produced by cells which induces healthy cells to manufacture enzymes to counter infection). It also protects neutrophils from poisoning themselves when attacked by bacteria. In addition, vitamin C may enhance NK cell activity as much as 10-fold and restore depleted T cell and B cell counts to healthy levels.¹ Vitamin C also assists the immune system by preventing oxidative damage. For example, a Spanish in vitro study demonstrated the addition of vitamin C to lymphocytes and macrophages increased intracellular levels of vitamin C, which was found to be especially useful under circumstances of oxidative stress.²

Vitamin C may also reduce the severity of symptoms and shorten the duration of the common cold, according to researchers from Herbal Health Centre in East Sussex, England. Scientists randomly administered 168 volunteers either vitamin C or placebo for 60 days. The treatment group experienced considerably fewer colds, fewer days of infection and a significantly shorter average duration of severe symptoms.³ The vitamin C used in the study was Ester-C®, supplied by Prescott, Ariz.-based Zila Nutraceuticals.

The carotenoid beta-carotene is a precursor of vitamin A and has been shown to modulate immune functions in humans. One German study showed supplementation with vegetable juice rich in betacarotene modulated immune function in healthy men consuming a low-carotenoid diet by enhancing activity of NK cells and secretion of cytokines, among other effects.⁵ Similarly, Pakistani researchers found human NK cells treated with beta-carotene at doses ranging from 0.1 mcg/ml to 10 mcg/ml showed a significant increase in activities against tumors and concluded beta-carotene works to inhibit growth factors that contribute to proliferation of pre-malignant cells.⁶

Several vitamins and minerals have been shown to support immune function. Vitamin D, for example, is recognized for encouraging macrophage activity. Meanwhile, vitamin E has been studied for its effect on the thymus and white blood cells, which may suffer from oxidative stress. Vitamin E has also been linked to improved cell-mediated immunity, enhanced cellular function and increased resistance to infection. Vitamin E also works in conjunction with vitamin C to increase T cell proliferation and reduce inflammation. Furthermore, according to the Manual of Nutritional Therapeutics, a deficiency of vitamin E reduces the response of T cells, NK cells and phagocytes, and reduces the proliferation of lymphocytes.⁷

Other vitamins recognized for their role in healthy immune function include the B vitamins, which aid in the synthesis of antibodies. Vitamin B6, in particular, is required to create antibodies and slow tumor growth. Deficiency leads to decreased cell-mediated immunity, lowered antibody response and decreased lymphocyte counts.⁸

Since various minerals play diverse, critical roles in the functioning of the immune system, their inclusion in a program of dietary supplementation is also important to immune support, according to Max Motyka, director of the Human Products Division at Albion Advanced Nutrition in St. Clair Shores, Mich. For instance, zinc, which acts as both a mineral and an antioxidant within the body, is crucial to immune function. Zinc encourages the proliferation of lymphocytes and the response of phagocytes, while zinc deficiency impairs overall immune function and resistance to infection.⁹ Specifically, a shortage of zinc within the body causes thymic atrophy, lymphopenia (i.e., an abnormally low white blood cell count), and reduced response of lymphocytes and antibodies, leading to increased incidence and duration of infection, according to a review study published in the Annual Review of Nutrition.¹⁰ As an antioxidant, zinc has been shown to act as a free-radical scavenger, thereby inhibiting cellular damage such as lipid peroxidation and DNA fragmentation, both in vitro¹¹ and in vivo.¹²

Zinc has also been linked to prevention of the common cold. A study, published in the American Journal of Therapeutics, was conducted during the cold season and found zinc lozenges were effective in reducing the incidence and duration of the common cold.¹³

Zinc monomethionine, a new form of supplemental zinc, is available as OptiZinc™ from Benecia, Calif.-based InterHealth Nutraceuticals Inc. Zinc monomethionine has been shown to assist immune function by enhancing phagocytic response, according to several unpublished studies, the company said. In addition, zinc monomethionine has been shown in clinical trials to have enhanced bioavailability compared to some other zinc forms.^14,15

The plant world is a prime source of immune-friendly compounds. Echinacea is one such botanical. Research conducted on echinacea has shown the herb improves immune function. A study conducted at the University of Alberta in Canada indicated rats given an oral preparation of echinacea twice daily for four days exhibited increased macrophage activity and an increase in tumor necrosis factor alpha.¹⁷

Echinacea has also been shown effective in treating the common cold. In a randomized, double blind, placebocontrolled Canadian trial, 282 subjects, aged 18 to 65 years, with a history of two or more colds in the previous year but otherwise in good health, were given either echinacea or placebo.¹⁸ The researchers concluded early intervention with a standardized formulation of echinacea resulted in reduced symptom severity in subjects with naturally acquired upper respiratory tract infections.

However, echinacea has not been found effective as a treatment for the common cold in all clinical trials, which has caused controversy over the herb’s worth as an immune-boosting supplement. A new study published in the June issue of The Archives of Internal Medicine recorded duration of symptoms in 128 patients with upper respiratory infections who received either 100 mg of freeze-dried echinacea from the aerial portion of the plant, or a lactose placebo, three times daily for 14 days or until cold symptoms desisted.¹⁹ The authors found no statistically significant differences between groups and were unable to validate earlier research indicating echinacea effectively reduces the symptoms and duration of the common cold.

Whereas most naturally occurring AGs are bound to cell walls, the AG found in the western larch tree (Larix occidentalis) is not bound and is present in higher concentrations than in other plant sources. Minnesota-based Larex Inc. offers this naturally concentrated source of larchderived AG as ImmunEnhancer™ AG. The product contains a concentrated, standardized form of AG, and is marketed for a number of immune-friendly benefits, including support of beneficial microflora populations in the colon and stimulation of various components of the immune system.

Human studies published in peer-reviewed literature indicate that taking ImmunEnhancer in amounts ranging from 1.4 g/d to 30 g/d can increase the production of monocytes, macrophages, neutrophils and lymphocytes, according to Kathleen Dunn, senior compliance manager with Natrol, which distributes ImmunEnhancer AG through its specialty division, Essentially Pure Ingredients (EPI). Further, results from in vitro and ex vivo studies indicate ImmunEnhancer AG promotes the proliferation of mononuclear cells, stimulates the activity of NK cells, and enhances neutrophil function, Dunn said.

Another source of beneficial polysaccharides is medicinal mushrooms. As with AG polysaccharides, the polysaccharides in mushrooms are also linked to improved immune function. Of the 700 varieties of mushrooms, approximately 50 have been found to have medicinal qualities. One such variety is the Brazilian mushroom Agaricus blazei Murill (ABM), which is believed to act as an anticarcinogen. Research suggests ABM exerts immuneenhancing effects through stimulation of antibody production and T cell proliferation.

ABM is offered commercially by Redondo Beach, Calif.-based Atlas World USA as Agaricus Bio (capsules) and Agaricus Extract Mate (ABM and sasa bamboo leaf extracts). The ABM used in these formulations contains beta-1,3/1,6-glucans, which have been shown to act as immunostimulants in the body, and has antitumor, antiviral, bloodsugar stabilizing and cholesterol-reducing effects, according to Yori Takeda, marketing and sales manager with Atlas.

The chief polysaccharide in maitake, beta- D-glucan (studied as Maitake D-fraction® from Maitake Products) has been studied in numerous clinical trials as a potential tool for cancer prevention and treatment. For example, a study conducted at the Kobe Pharmaceutical University in Japan showed that D-fraction enhances the activity of NK cells to suppress tumor growth by increasing macrophage-derived interleukin (IL)-12, which serves to activate NK cells.²² Similarly, the same Japanese researchers in a different study found Maitake D-Fraction may repress cancer progression through stimulation of NK activity.²³ The same researchers investigated maitake MD-fraction and whole maitake powder in a non-random case series to determine its effectiveness for 22- to 57-yearold cancer patients in stages II-IV of cancer and observed cancer regression or significant symptom improvement in 58 percent of liver cancer patients, 69 percent of breast cancer patients, and 63 percent of lung cancer patients. ²⁴ Furthermore, the researchers found when maitake was taken in addition to chemotherapy, immune-competent cell activities were enhanced 1.2 to 1.4 times, compared with chemotherapy alone.

“AHCC is shown through clinical research to enhance the immune system by increasing the activity and count of the lymphocytes and cytokines,” said Hank Cheatham, director of sales and marketing for QOL.

AHCC can be used as a potent immunoenhancer, particularly in cases where the immune system is suppressed by any condition, including opportunistic infection amongst HIV patients and cancer, according to researchers at the Atlanta-based Morehouse School of Medicine.²⁵ With regard to the efficacy of AHCC in the eradication of opportunistic infection, the Morehouse School of Medicine researchers mentioned previously found AHCC decreased mortality, increased time to death and increased ability to clear infection in mice infected with Klebsiella pneumonia bacteria and maintained in a model simulating some of the aspects of spaceflight conditions, and concluded AHCC can help boost depressed immunity and resistance to infection.²⁶ In addition, scientists at the Teikyo University School of Medicine found oral or intraperitoneal administration of AHCC at doses of 1,000 or 50 mg/kg/day, respectively, for four consecutive days prior to Candida albicans infection significantly prolonged the survival periods of the opportunistically infected mice, and decreased the viable counts of Candida cells recovered from their kidneys.

Beyond polysaccharides, there are other beneficial compounds in plants. For instance, as animals produce cholesterol, plants produce phytosterols, including sterol esters and sterolins, which have been shown to produce immune-modulating benefits. Phytosterols are similar in chemical structure to cholesterol, but have an extra ethyl group.

Phytosterols modulate the immune system by helping to maintain the proper balance between two types of T-cells (i.e., TH1 and TH2 cells) required for optimal immune function. When the balance between these cells becomes skewed, impaired immunity results. These fats also help maintain a high population of T cells by enhancing their ability to proliferate. Plant sterols also stop the secretion of inflammatory antibodies by encouraging the secretion of two more immune factors.

The bioavailability of phytosterols has historically been poor, since plant sterols occur naturally in very small amounts, are not well-absorbed and are often destroyed through food processing. However, Acton, Ontario-based Essential Phytosterols Inc.

(EPI) has developed the technology to synthesize a highly bioavailable source of phytosterols as Moducare®, a patented blend of concentrated plant sterols and sterolins marketed to restore, strengthen and balance the immune system. The sterols and sterolins in Moducare are formulated in the ratio of 100:1 (sterols to sterolins), as found in nature. Evidence backing the efficacy of the 100:1 sterols/sterolins ratio was published in the International Journal of Immunopharmacology.²⁷ In the in vitro study, researchers extracted T cells from the blood of healthy volunteers and incubated the samples for 72 hours with various dilutions of independent sterols, sterolins or the 100:1 sterol/sterolin mixture. The results suggested that the 100:1 sterol/sterolin mixture was more efficacious than either sterols or sterolins alone in inducing T cell proliferation. In the same journal, another study found the 100:1 sterol/sterolin proportion to be a potent immunomodulator with possibilities for treatment of immune dysfunction.²⁸

“Moducare is different than many other products on the market in that it doesn’t just boost the immune system—it regulates the immune system,” said Michael Wagner, associate brand manager with Purity Life Health Products Ltd., which distributes Moducare. “It strengthens the weak parts of the immune system and down-regulates the overactive parts.”

The ability of pine bark extract to enhance the immune system was shown in a study conducted at the University of Arizona.³¹ Researchers infected mice with a virus, investigated the immune response with and without pine bark extract supplementation (as Pycnogenol), and found a dramatically improved immune response in those animals orally supplemented with pine bark extract.

In humans, pine bark extract (as Pycnogenol) was shown in a controlled Romanian study to lower blood levels of antibodies and the aggressiveness of immune cells attacking the body in patients with the autoimmune disease lupus. Pine bark extract was also found to improve the breathing ability of patients with asthma in a double blind placebo-controlled study conducted at the University of Arizona.³²

The gel of the aloe plant (Aloe barbadensis) is known commonly as a topical treatment for skin burns and inflammation. In addition, aloe contains acemannan, a complex carbohydrate fraction obtained from the gel of the aloe leaf. Acemannan is thought to be anticarcinogenic and antiviral, and enhance immune function, although the biological mechanisms of these activities remain unclear.

Acemannan may affect the immune system through stimulation of macrophage cytokine production. Researchers from Texas A & M University, Department of Veterinary Pathobiology, tested this idea by observing the effects of acemannan on mouse macrophage cells and concluded the results of the experiment supported this hypothesis.³³

Other research has suggested the presence of a beneficial relationship between acemannan and the immune system. Scientists from Chungbuk National University in South Korea studied acemannan’s effects on dendritic cells, which help initiate primary immune response.³⁴

According to the scientists, acemannan was able to promote the maturation process of these cells in vitro. Another study out of Nashville, Tenn.-based Vanderbilt University studied acemannan for its impact on the ability of T cells to kill a certain antigen and found acemannan induced dose-related, statistical increases in killer T cell populations.³⁵ The same researchers in a different study found that acemannan increases lymphocyte response and concluded the data supported the observed capacity of acemannan to terminate viral infections in animal and man.³⁶

Acemannan is available from Irving, Texas-based Carrington Laboratories as Manapol®, a patented compound derived from the inner leaf of the aloe plant. Manapol contains 30 percent acetylated mannans, including acemannan and other galactomannans. “Acetylated mannans, like those found in fresh Aloe vera L. gel and Manapol powder, have shown powerful immunomodulating properties,” said Walt Jones, vice president of business development with Carrington.

There are other specialty nutritional compounds that may benefit immune function. Consider immunoglobulins, which are found in colostrum, a pre-milk fluid produced in the mammary glands of female mammals prior to giving birth. These antibodies provide proteins, growth factors and other compounds that help jump-start an infant’s immune system.

Purified bovine serum is another source of immunoglobulins. Shawnee Mission, Kan.- based NutraSense offers a concentrated source of natural immunoglobulins, immunoregulators, transferrin and growth factors as ImmunoSense™, formulated with ImmunoLin-HD™, Ames, Iowa-based Proliant’s bovine serum protein ingredient which contains 40 percent immunoglobulin G (IgG), or 500 percent more IgG than colostrum.

Supplementing with immunoglobulin may guard against infection in a number of ways. First, immunoglobulin neutralizes antigens. Second, it coats the surface of foreign materials to facilitate uptake by phagocytes, both in the blood and in the gastrointestinal (GI) tract. Third, supplementation with immunoglobulin has been linked to preservation of the normal protective barrier of the GI tract.

“The majority of products in the market take weeks to enhance immunity, not quite what the immune product shopper has in mind,” said Eric Weaver, Ph.D., president and chief executive officer (CEO) of Proliant. “This is one of the reasons we see a great opportunity for passive immunity products such as ImmunoLin. Consumers with immune issues don’t need to take the product for weeks to feel a benefit.”

Other animal-derived compounds are alkylglycerols, which occur in the bone marrow, breast milk and liver of mammals. Their intake helps support proliferation of white blood cells. In clinical research, alkylglycerols have demonstrated a cytotoxic effect upon cancer cells, and an ability to prevent metastases (i.e., spread of tumor cells to other sites). One of the most concentrated sources of alkylglycerols is shark liver oil, which also contains small amounts of methoxysubstituted alkylethers, compounds that stimulate the immune system and inhibit growth of malignant tumors. Shark liver oil is available as Ecomer® from Sellersville, Pa.-based Scandinavian Formulas.

“Many studies have shown that Ecomer stimulates the immune system by increasing the production of white blood cells to normal levels and encouraging growth of antibodies,” said Sylvie Millet, advertising/marketing coordinator with Scandinavian Formulas.

In a Swedish study conducted on shark liver oil (as Ecomer), alkylglycerols and their methoxyderivates showed a clear apoptotic and necrotic effect on human prostate and mammary carcinoma cell lines.³⁷ The anticarcinogenic properties of alkylglycerols were further demonstrated in a Polish study, in which Ecomer suppressed the formation and differentiation of blood vessels in mice grafted with sarcoma L-1 syngeneic cells, human kidney cancer and human urinary bladder cancer cells, and stimulated proliferation and metabolic activity of granulocytes (white blood cells involved in immune function).³⁸

The amino acid glutamine—the most prevalent amino acid in the body—is involved in more metabolic processes than any other amino acid and is crucial to tissue repair. Since 70 percent of immune activity occurs in the GI tract, and since the cells lining the intestines would wither without glutamine as a source of fuel, glutamine is important to immune function.

Glutamine is linked to immune function in additional ways. For example, it may enhance the phagocytic activity of macrophages, preserve CD4+ cells (a variety of T cells) and maintain T cell population in the blood, according to a Chinese study published in the British Journal of Nutrition.³⁹

Exercise depletes glutamine, which prevents white blood cells from functioning optimally.40 Maintaining high levels of glutamine in the body is therefore crucial to recovery of the immune system following exercise, according to Catherine Wilbert, president and product formulator with Phytoceutical Formulations. Wilbert’s company manufactures Bioactive Glutamine, a proprietary blend of bioactive glutamine and other ingredients. According to Wilbert, a deficiency of glutamine within the body causes it to catabolize its own muscle tissue to free glutamine, and supplementation with glutamine is a strategy to prevent this from happening.

“Bioactive Glutamine is more bioavailable than other types of glutamine, which allows more glutamine to get absorbed and used. Unlike other sources of glutamine, the product’s delivery system and prebiotics that support friendly intestinal flora enable enhanced gastrointestinal and other benefits of glutamine,” Wilbert said. “And a healthier gastrointestinal system equals healthier immune function.”

Another weapon in the body’s fight against free radicals is superoxide dismutase (SOD), a vital endogenous antioxidant enzyme known to assist with immune function. Its chief function is to disarm superoxide anion radicals, which tax the immune system by causing cellular damage that leads to the progression of diseases.

Historically, a viable oral delivery method for SOD has eluded scientists due to the proclivity of the enzyme to denature when exposed to gastric secretions. However, a technological breakthrough has made SOD as an oral supplement viable. Morristown, N.J.-based P.L. Thomas has proposed a solution to the limitations of exogenous SOD with GliSODin™, the first orally delivered, vegetarian source of SOD clinically shown to help the body maintain normal levels of the three endogenous enzymes most critical in regulation of free radicals at the cellular level: SOD, catalase and l-glutathione peroxidase.

“SOD is the master defense enzyme when it comes to protection against the ravages of excessive free radicals,” said Paul Flowerman, president and CEO of P.L. Thomas. “GliSODin supports the body’s own immunological defenses to maintain a healthy immune system.”

According to Flowerman, various animal and human studies accepted for publication have demonstrated GliSODin’s ability to reduce oxidative stress in humans. For example, subjects dosed with GliSODin for several weeks before entering an accelerated oxidative stress chamber were protected significantly from cellular DNA damage in comparison to subjects not dosed with GliSODin. Iso-prostain levels in the subjects’ urine were also reduced by prior GliSODin dosing, indicative of reduced oxidative stress. Another study showed GliSODin caused a reduction in lactate levels in blood serum after strenuous exercise conducted on 44 subjects, Flowerman said.

In addition to adopting a healthier lifestyle, many of the diseases caused by pathogens may be prevented through treatment with dietary supplements. However, these products require the retailer to develop a basic understanding of immune function and to maintain continual awareness of the latest research. As individuals differ in their immune needs, not every product is appropriate for everyone.

Nevertheless, providing immune-friendly supplements is a promising venture, in spite of the extra effort required to safely and effectively market them. Pathogens are growing increasingly hardy, new viruses are appearing and threats of bio-terrorism loom. In addition, the population of aging baby boomers in need of immune support is increasing, as is the mounting popularity of using complementary and alternative medicine (CAM) to support optimal immune function.

With these dynamics in motion, and with the proliferation of research backing the efficacy of various supplements, the market for immune supplements is thriving.

August 2004 Health Supplement Retailer
"Immune Function" References

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