The Immune Function
by Kim Schoenhals
The immune system is an incredibly intricate arrangement that prevents infection and disease by moderating malignant and foreign cells within the body. Many unwanted cells are simply devoured by the body's scavenger cells, although particularly stalwart adversaries take longer to destroy. While the immune system works to fend off these would-be invaders, the human host takes ill--fever and inflammation are some outward signs of the body's inner fight.
During advancing years, times of high stress or inadequate nutrition, the body's immune cells can become sluggish and less effective. When this happens, opportunistic invaders settle down to stay, potentially leading to serious infections, pneumonia or cancer.
The immune system is composed of several organs and systems, as well as various types of immune cells. Organs that constitute the immune system--called lymphoid organs--include the spleen and thymus. Additional components of the immune system are lymph nodes and bone marrow.
Within bone marrow, lymphocytes (white blood cells) are born to function as immune cells. Neutrophils are the main circulating white blood cells, which seek out invaders when they are summoned into action by other immune cells. They secrete toxins that kill antigens (invading proteins) and devour them.
The two major classes of lymphocytes are B-cells, which mature in the bone marrow and reside in the lymph system, and T-cells, which mature in the thymus and circulate throughout the body. B-cells are responsible for producing antibodies (a.k.a. immunoglobulins), which are proteins designed to recognize and mark a specific antigen, while T-cells are charged with destroying antigens that are tagged with an antibody.
There are three types of T-cells: cytotoxic T-cells, helper T-cells and suppressor T-cells. Cytotoxic T-cells attach themselves to malignant or infected cells. They secrete interferons, which stop viruses from reproducing. Helper T-cells--including TH1 and TH2--assist cytotoxic T-cells by recognizing an attack on the body, at which point cytotoxic T-cells are sent to fight the infection. Helper T-cells also help the body's B-cells produce antibodies. Suppressor T-cells are responsible for regulating the body's immune response to invasions; they stop cytotoxic T-cells from releasing cytokines (immuno-regulatory substances) and stop the production of immunoglobulins.
Immunoglobulins exist in five classes: IgA, IgE, IgG, IgM and IgD. IgA is responsible for holding off invaders or pushing them out of the body, which is why it exists in tears, milk, sweat and saliva. IgE is involved in allergic reactions and encourages mast cells to release histamine, as well as triggering inflammatory response. IgG is specialized to kill certain bacteria and viruses, and activates enzymes that digest invaders. IgM circulates in the bloodstream to kill bacteria. Finally, IgD circulates in the blood system, but not much is known on its particular function.
Additional immune cells are scavenger cells called phagocytes--which include granulocytes and macrophages. These cells seek out and devour invading cells. Macrophages are generally stationary and protect a specific area, although they are also known to travel to a point of infection to assist in warding off an antigen. They release pyrogen, a substance that signals the body to increase temperature to induce fever, which is oftentimes useful for killing pathogens.
Another scavenger, the natural killer (NK) cell, destroys invaders without seeking out B-cells' tags. NK cells search for foreign cells and kill them by releasing toxic enzymes and interferons.
Just as NK cells secrete interferons, other immune cells secrete interleukins, another type of cytokine, or immuno-regulatory substance. These substances, which include monokines (secreted by monocytes) and lymphokines (secreted by lymphocytes), are responsible for regulating the body's immune response, such as the magnitude of an inflammation.
Interleukins, which are secreted by macrophages, monocytes and some T-cells, include more than 30 types. Interleukin-1 is produced by macrophages and is involved in inducing fever, which can kill or slow down a virus or bacterium. Interleukin-2 assists helper T-cells in encouraging cytotoxic T-cells to kill invaders. Interleukin-4 enhances the B-cells' ability to make antibodies (IgG and IgE in particular), and it stimulates helper T-cells and cytotoxic T-cells. Interleukin-6 is released by macrophages, monocytes and some T-cells, and induces B-cells to produce antibodies.
Tumor necrosis factor (TNF) is released by macrophages to induce fever. It can kill cancer cells and promotes the production of lymphokines.
With all of these cells and processes for fending off invading microbes, fungi, bacteria and viruses, the immune system has its work cut out for it, and there are numerous outward factors that can disrupt the body's process of fighting off infection. Immunity can be disturbed through anxiety1 and depression,2 as well as malnutrition.3 According to data from the Natural Marketing Institute's (NMI) Health and Wellness Trends Database--three years of trended data including more than 2,000 household respondents--more than half of immune sufferers are also managing or treating stress, lack of energy, joint pain and stiffness, and sleeplessness.
Because malnutrition adversely affects immune function, ensuring proper nutrition through the diet is essential to protecting and maintaining the immune system. In addition to nutrient intake, several botanical and nutritional substances work to enhance the various activities that make up immune function.
"Micronutrient starvation is a silent foe--its harmful effects may not be felt for years, yet it is the No. 1 cause of poor immune function and, therefore, disease," wrote Robert Rountree, M.D., and Carol Colman in Immunotics (G.P. Putnam's Sons, 2000). "Micronutrients include vitamins, minerals and important chemicals found in plant foods (called phytochemicals). Some micronutrients are well known, such as vitamin C and calcium, while others may be less familiar, such as carotenoids and bioflavonoids. ... Numerous studies have documented that when blood levels of key vitamins, minerals and phytochemicals drop below optimal levels, our immune systems don't function properly."
Antioxidants, those nutrients known for combating free radical damage, are suggested for improving and maintaining a healthy immune system. According to a research review out of GlaxoSmithKline Consumer Healthcare in Parsippany, N.J., antioxidant micronutrients have been consistently found to enhance lymphocyte proliferation, especially in the elderly.4
Vitamin C, an antioxidant vitamin, exists in lymphocyte and macrophage cells. Consumers seeking a boost in immune function often turn to vitamin C, according to NMI data. While 45.4 percent of the general population takes a vitamin C supplement, 67.8 percent of immune sufferers take the vitamin.
Researchers from Complutense University in Madrid, Spain, conducted an in vitro experiment that demonstrated when vitamin C was added to lymphocytes and macrophages, both types of cell showed an increase in the intracellular levels of vitamin C, which was found to be especially useful under oxidative stress conditions.5
A human trial conducted by researchers at Karl-Franzens University Graz in Austria indicated vitamin C supplementation does not necessarily correct neutrophil dysfunction brought on by exercise. They gave six athletes 2 g/d of vitamin C for one week prior to a competition and compared their immune function to four athletes who took no supplements. All athletes suffered a significant reduction in neutrophil ability, and no differences were noted between the groups.6
Similar to vitamin C, vitamin E is also popular among immune sufferers, according to NMI. While 45.7 percent of the general population supplements with vitamin E, 50.8 percent of immune sufferers do.
Taken together, vitamins E and C were found to be effective adjuvant therapy for enhancing neutrophil performance in patients with systemic vasculitis (inflamed lymph nodes). Researchers from Birmingham University in England found that by treating patients with vitamins E and C, neutrophil generation of superoxide was reduced, suggesting antioxidants are important for treating vasculitis.7
In vitro research with vitamin E indicated that the nutrient stimulates NK cell function. Researchers at Aga Khan University in Karachi, Pakistan, also conducted animal research with vitamin E. They learned that mice supplemented with 100 mg/d of alpha-tocopherol developed increased NK cell activity. And, tocotrienol showed a similar response at ten times lower a dose.8
Vitamin E was also found to improve the immune function in patients with colorectal cancer. Researchers from Karolinska Institutet in Stockholm, Sweden, administered 750 mg/d of vitamin E to 12 patients for two weeks, after which time subjects exhibited increased T-cell ratios and a 10-percent increase in the number of T-cells producing interleukin-2, compared with blood levels prior to treatment.9
Coenzyme Q10 (CoQ10) is another micronutrient with antioxidant effects that has been indicated in enhancing immune function. According to in vitro research out of the University of Ancona in Italy, exposing human lymphocytes to ubiquinol-10 (the reduced form of CoQ10) or CoQ10 enhanced DNA resistance toward hydrogen peroxide-induced oxidation.10
In vivo research conducted by scientists at the University Hospital Sant'Orsola-Malpighi in Bologna, Italy, indicated CoQ10 concentrations are positively associated with NK cell cytotoxicity in women. Researchers also noted elderly subjects (aged 90 to 106 years) tend to have inadequate CoQ10 status--in 40 percent of women and 24 percent of men.11
Selenium, an antioxidant mineral, also has application in the realm of immune function. According to the Bologna researchers, serum selenium concentrations were associated with the presence of NK cells. In addition, researchers at the University of Surrey in Guildford, England, noted selenium deficiency had adverse effects on immune function, and supplementation with the mineral was associated with enhanced immune response.12
Selenium deficiency may allow invading viruses to mutate and remain for a longer period in the host. This effect was demonstrated by researchers at the University of North Carolina in Chapel Hill and colleagues. They compared mice that received a selenium-deficient diet with non-deficient animals, all of which were exposed to the human influenza virus. The deficient mice had more severe cases of the flu that lasted for a longer period of time, characterized by lung inflammation, than the non-deficient mice.13
Selenium supplementation has been shown to influence immune response, and when combined with vitamin E, selenium's effects are more powerful, according to researchers from the University of Hong Kong. They demonstrated that vitamin E and selenium have interactive effects as oxygen radical scavengers, thereby promoting human lymphocyte response to antigens.14
Alpha-lipoic acid, a powerful antioxidant, is a vitamin-like, sulfur-containing compound that may improve immune function. Alpha-lipoic acid's effect on immunity may be due to its ability to promote the secretion of interleukin-2, according to researchers from the University of Sydney. Through in vitro research, they demonstrated alpha-lipoic acid preferentially induced apoptosis (cell death) among leukaemic T-cells.15
Alpha-lipoic acid is also able to recycle other antioxidants, including vitamins C and E, CoQ10 and glutathione, another sulfur-containing compound. Levels of glutathione determine macrophage, phagocyte and lymphocyte activity. Researchers from Tokyo University of Science studied NK cell activity in mouse splenocytes that were zapped with low dose gamma rays. They found that adding glutathione to splenocytes enhanced the total cellular glutathione content and NK cell activity in a dose-dependent manner.16
In addition to the antioxidant micronutrients, there are many vitamins and minerals that have been shown to improve immune function. Vitamin D, for example, is known for stimulating macrophage activity. And, the B vitamins are known to help the body metabolize food into energy and synthesize antibodies for the immune system. Vitamin B6, for example, is required to create antibodies and slow tumor growth. Additionally, deficiencies of several nutrients, including vitamin A, zinc and iron, are known to exist in populations where infectious disease is a major health concern.17
Vitamin A deficiency has been linked with immunity issues during pregnancy, according to researchers at the Rowett Research Institute in Scotland. Their animal research demonstrated that vitamin A deficiency during pregnancy caused abnormal placental apoptosis because the mother's neutrophils were deprived of TNF-alpha.18
Zinc is an essential trace element that influences the growth and integrity of the immune system, according to a research review out of Universite Paris V Hopital Necker. Zinc impacts key immune mediators, including enzymes, thymic peptides and cytokines, explaining the importance of zinc status on lymphocyte activity.19
Researchers at the University of California, Berkeley, studied the effects of a zinc-restricted diet on eight healthy men and determined changes in lymphocyte proliferation and interleukin-2 expression were possibly early markers of mild zinc deficiency.20
Unpublished animal research out of North Carolina State University in Raleigh showed that a zinc-methionine complex (as OptiZinc™, manufactured by Benicia, Calif.-based InterHealth Nutraceuticals Inc.) was able to enhance mononuclear-phagocytic function, which is important for disease resistance and increased cellular immunity.
Iron is another mineral that is necessary for optimal immune response. Although iron is part of the antioxidant enzyme catalase, it is not generally considered an antioxidant. In fact, an excess of intracellular iron can increase the production of free radicals, according to researchers at the Karolinska Institute in Stockholm, Sweden. They conducted in vitro research and discovered that excess iron levels also decrease the efficacy of TNF-alpha in protecting against liver cell damage.21
While excess iron can cause damage, the mineral is necessary for optimal immune function, as it is crucial for lymphocyte and interleukin-2 proliferation, according to researchers from Louisiana State University in Baton Rouge. They conducted in vitro research and found iron affects an early step of T-cell activation.22
Copper is an essential trace mineral that is a cofactor in various enzyme systems and is required for the maintenance of immune function. According to researchers at the University of Ulster in Coleraine, Ireland, various immunological markers have the potential to highlight marginal copper status. Some of the markers that may lend insight to copper status include neutrophil function, interleukin-2 production, blastogenic response to mitogens and lymphocyte subset phenotyping.23
Researchers from Oklahoma State University, Stillwater, conducted a human study to determine the effects of copper and chromium supplementation on immune function. They divided 40 postmenopausal women with high cholesterol into four groups: 1) 200 mcg/d of chromium; 2) 3 mg/d of copper; 3) both copper and chromium at the same levels; or 4) .394 g/d of lactose as control. After 12 weeks, researchers noted a significant interactive effect of chromium and copper supplementation on lymphocyte proliferation, which was stimulated by the researchers. Lymphocyte proliferation was significantly lower when copper was added to the chromium group, and lymphocyte proliferation was significantly lower in the copper supplementation group compared to the chromium group. Researchers concluded copper blocks enhancement of lymphocyte proliferation by chromium supplementation, and copper supplementation had suppressive effects on immune function in this study population.24
Immune Sufferers Are Generally Less Well Than GP
©The Health & Wellness Trends Database.
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Carotenoids and Flavonoids
Carotenoids are fat-soluble pigments derived from plants that exhibit antioxidant properties and have been studied in the realm of immune function. According to researchers at the Institute of Nutritional Physiology in Karlsruhe, Germany, consuming a carotenoid-rich diet can moderate T-cell function. In addition, dietary carotenoid intake can influence the secretion of cytokines from helper T-cells, just as low carotenoid intake can suppress this function.25
Lutein, one of the more well-known carotenoids, naturally occurs in corn and spinach, although it is derived from marigolds for commercial use. Animal research out of Washington State University in Pullman indicated dietary lutein stimulates both cell-mediated and humoral (non-cellular) immune responses. Female dogs fed dietary lutein for 12 weeks exhibited increased lymphocyte proliferation and production of IgG.26 A similar study conducted by the same team with female cats indicated those cats fed dietary lutein for 12 weeks demonstrated an immunomodulatory response.27
Lycopene, a carotenoid found in high concentrations in tomato and tomato-based products, is a powerful antioxidant and may be able to protect immune cells from oxidative damage, according to researchers at the University of Milan in Italy. They administered 25 g/d of tomato puree (containing 7 mg of lycopene) to nine adult women and evaluated the ability of lymphocytes to withstand oxidative damage. Results indicated intake of tomato puree increased plasma and lymphocyte lycopene concentrations, and reduced lymphocyte DNA damage by approximately 50 percent.28
Aside from its antioxidant capacity in protecting immune cells, lycopene may not increase immune cell function. A study conducted by researchers at University College in Cork, Ireland, failed to associate supplementation with low levels of lycopene (13.3 mg/d) with beneficial effects on cell-mediated immunity. The researchers administered either lycopene, beta-carotene (8.2 mg/d) or placebo to 58 elderly subjects. After 12 weeks, researchers did not find beneficial or detrimental effects on immune function in any of the groups.29
On the other hand, beta-carotene, a carotenoid precursor of vitamin A, has been found to increase NK cell activity. Researchers at Aga Khan University conducted an in vitro study and determined that cells treated with beta-carotene at doses ranging from .1 mcg/ml to 10 mcg/ml showed a significant increase in tumorolytic function--the ability to inhibit pre-malignant cells. However, in doses of 2 ng/ml to 200 ng/ml, cells exhibited a decrease in tumorolytic effects.30
A placebo-controlled study of beta-carotene out of the University of Maryland in College Park garnered similar discouraging results. Short-term beta-carotene supplementation (30 mg/d for 28 days) during early lactation did not enhance T-cell immune competence in healthy women, although it was found to increase plasma concentrations of beta-carotene and alpha-carotene.31
Astaxanthin, a carotenoid derived from algae, is also thought to enhance NK cell activity. Researchers at the Institute for Health Care Science in Osaka, Japan, discovered that stress reduced NK cell presence and caused liver tissue damage in mice. However, when the animals were given daily oral astaxanthin, it markedly slowed liver tissue damage.32
Additional animal research conducted at the University of Minnesota in Minneapolis demonstrated similar findings. Astaxanthin-fed mice exhibited an increased resistance to tumor growth, as well as higher cytotoxic T-cell and interferon-gamma activity, compared to control mice that received none.33
Flavonoids, or bioflavonoids, are similar to carotenoids in that they are plant pigments, although they are water-soluble rather than fat-soluble. Flavonoid compounds are included in a class of substances called polyphenols.
Proanthocyanidins--a class of flavonoids also known as leucocyanidins, procyanidolic oligomers (PCOs) or oligomeric procyanidins (OPCs)--exert antioxidant properties and are an active constituent of grape seed extract.
Grape seed extract may enhance the growth and viability of the normal human gastric mucosal cells and murine macrophage cells. And, its proanthocyanidins are known to have anti-inflammatory properties by inhibiting the degradation of mast cells (which release histamine).
Grape seed extract also appears to induce gamma interferon, which is derived from helper T-cells (TH1), according to researchers at the State University of New York at Buffalo. They conducted in vitro research and discovered a grape seed extract exerted significant anti-tumor and antiviral effects by inducing production of gamma interferon.34
Another derivative from the grape, resveratrol is a polyphenol purported for its heart-healthy properties. Research out of the Institute of Experimental Medicine in Rome indicated resveratrol also moderates several human immune cell functions. Cells exposed to resveratrol at low levels were stimulated to produce interferon gamma, interleukin-2 and interleukin-4, while high concentrations of resveratrol suppressed this effect.35
Similar to grape seed extract, cranberries contain proanthocyanidins. Cranberries also contain additional flavonoids--flavonols and anthocyanins. According to researchers at the University of Wisconsin, Madison, the immunomodulatory effects of the flavonoids derived from cranberries may be responsible for their use in preventing heart disease. They hypothesized flavonoid intake could affect immune response to oxidized low-density lipoprotein (LDL) and its uptake by endothelial macrophages.36
Bilberry also contains a flavonoid complex that exhibits antioxidant function. Anthocyanidins, the active constituents of bilberry, are thought to prevent inflammation and are mediators of the immune substances that initiate inflammation such as histamine, protease, leukotrienes and prostaglandins. The Commission E--a German committee charged by the federal health agency with reviewing the safety and efficacy of phytomedicines--approved internal use of bilberry to treat mild inflammation of the mucous membranes of the mouth and throat.
Another extract that contains flavonoids is pine bark. Specifically, pine bark extract contains OPCs and phenolic acids, and is touted for its antioxidant properties. Researchers from the University of California, Berkeley, noted French maritime pine bark extract (as Pycnogenol®, distributed in North America by Hillside, N.J.-based Natural Health Sciences) has strong free radical-scavenging activity, which is fostered significantly by its OPCs.37
The same Berkeley researchers conducted a study of French maritime pine bark as it relates to immune function. They learned that the extract increased TNF-alpha secretion in a concentration- and time-dependent manner. Researchers also said the OPCs modulated immune response in macrophages.38
A pilot study conducted as a collaboration between the University of Bucharest in Romania and the University of Munster in Germany indicated French maritime pine bark (as Pycnogenol) has immunoregulatory effects and may be beneficial for patients with the autoimmune disease lupus. Six patients given the extract in addition to their regular therapy exhibited a significant increase in lymphocyte lifetime compared to five patients who remained on traditional therapy alone.39
Similar to OPCs and anthocyanins, soy isoflavones are considered flavonoids and exhibit antioxidant effects. Researchers at the Food Research Program in British Columbia conducted a research review of flavonoid compounds and their effects on the production of TNF-alpha. They learned that the soy isoflavone genistein inhibited TNF-alpha production, while the isoflavone daidzein enhanced production.40
In a human trial, researchers at St. Michael's Hospital in Toronto treated 41 hypercholesterolemic men and postmenopausal women with one of three diets: 1) low-fat dairy; 2) high-isoflavone (50 g/d of soy protein with 73 mg/d of isoflavones); or 3) low-isoflavone (52 g/d of soy protein and 10 mg/d of isoflavones). After one month, the women demonstrated significantly higher interleukin-6 values after the high-isoflavone diet compared to control values. Researchers concluded this finding may indicate an estrogenic effect of soy isoflavones in enhancing immune response and may explain the lower incidence of certain cancers through immune surveillance in soy-eating parts of the world.41
Green and black tea contain polyphenolic compounds that have antioxidant properties and have been studied for their effects on immune function. Researchers at Case Western Reserve University in Cleveland conducted animal research with (-)-epigallacatechin-3-gallate (EGCG), a phenolic compound extracted from green tea, and discovered that topical application protects against UVB-induced immunosuppression in mice. Researchers found that EGCG, when applied to the skin before exposure to UVB light, reduced the number of monocytes, macrophages and neutrophils that infiltrated skin inflammatory lesions, which may be responsible for creating UVB-induced immunosuppression.42
The same researchers continued this line of study and learned that pretreatment with EGCG decreased oxidative damage to the skin and prevented UVB-induced immunosuppression and skin cancer incidence.43
Another study out of the Institute of Radiation Medicine in Beijing, China, indicated a possible protective effect against cancer with green tea supplementation. When mice induced with Lewis lung carcinoma were treated with green tea, mixed tea or tea polyphenol, the tea components prohibited immune dysfunction and protected against exposure to the carcinogen. In addition, researchers noted improved immune function in all mice receiving green tea.44
Immune Suferers Turns to Vitamins, Mineral and Herbal Supplements at a Higher Rate Than GP ©The Health & Wellness Trends Database.
The Natural Marketing Institute, 2002
Several medicinal mushrooms and their derivatives have been studied for their immune-enhancing properties. "Just how mushrooms help stimulate the body's immune system is a matter of controversy," wrote Harry Preuss, M.D., and Sensuke Konno, Ph.D., in Maitake Magic (Freedom Press, 2002). "Most experts agree that a key to their immune-stimulating properties is their content of polysaccharides--beta-glucans--that in experimental and clinical studies have shown potential for boosting immunity and preventing cancer."
Maitake (Grifola frondosa) is a medicinal mushroom purported for its ability to improve immune function. Specifically, the mushroom's beta-glucans are thought to enhance macrophage function. "Beta-glucans impact a type of non-specific or generalized immune enhancement by supporting the most fundamental aspect of immune function--the primitive, yet all-powerful, macrophage," Preuss and Konno wrote. "Indeed, beta-glucans appear to be essential to optimal immune function for virtually all life forms. They are especially helpful against viral infections."
Specifically, the polysaccharides derived from Maitake are thought to improve a patient's fight against HIV and AIDS by preventing HIV-infected helper T-cells from dying, according to Preuss and Konno. In addition, the authors noted Maitake can help stabilize T-cell counts in HIV and AIDS patients, as well as improve levels of interleukin-1 and -2.
Researchers at Kobe Pharmaceutical University found Maitake's beta-1,6 glucan and beta-1,3 glucan taken in addition to chemotherapy enhanced immune cell activity by 1.2 to 1.4 times compared to chemotherapy alone.45 Some of the same researchers sought to find how Maitake inhibits tumor formation and found Maitake promoted TNF-alpha production.46 In another study, they noted Maitake established immune balance between TH1 and TH2 cells, thereby inducing cellular immunity in patients with an abundance of TH2 cells due to cancer.47
Another medicinal mushroom studied for its immune-enhancing and anti-tumor powers is Reishi (Ganoderma lucidum), which contains active polysaccharides and is purported to act as an antioxidant. A group of researchers from Hiroshima University in Japan conducted two animal studies and concluded from both that a water-soluble extract from a cultured medium of Reishi may act as a preventive agent against colon cancer.48 The second study involved mice that were induced to cancer and then fed either a diet with 5 percent Reishi or none for 10 weeks. Researchers noted a significant reduction in tumor size in the Reishi group compared to control.49
Shiitake (Lentinus edodes) is another medicinal mushroom that has been studied in the realm of immune function because of its polysaccharide content. Shiitake is touted for improving immune function by activating macrophages, promoting the recognition of antigens, increasing interleukin-1 production, promoting the growth of B-cells and increasing antibody production.
Researchers at the National University of Singapore determined that an aqueous extract of Shiitake decreased interleukin-1 production and apoptosis in human neutrophils and was found to increase interleukin-1 production and apoptosis in another line of immune cells.50
Another medicinal mushroom that is said to have immune-enhancing properties is Agaricus blazei (Himematsutake), which is also thought to act as an anticarcinogen. Mice were implanted with two tumors, one of which was injected with an Agaricus blazei Murill extract. Researchers saw a regression in both the injected and non-injected tumors, and cited an activation of macrophages and neutrophils, as well as an increase in serum levels of immunosuppressive acidic protein.51
Researchers at Kobe University in Japan determined that orally administered Agaricus blazei also has anticarcinogenic potential. They treated mice with either a hot, water-soluble fraction from the mushroom or saline solution. Mice receiving the polysaccharide mixture exhibited anti-tumor activity and increased activity of cytotoxic T-cells.52
AHCC® (Active Hexose Correlated Compound), a hybridization of several species of medicinal mushrooms, has also been studied for its immune-enhancing properties and anticarcinogenic effects. (Editor's note: Amino Up Chemical Co. in Sopporo, Japan, owns the trademark for AHCC; Purchase, N.Y.-based Maypro Industries distributes the raw material.)
AHCC is thought to protect against cancer through its immune-enhancing effects. Recent research out of Kansai Medical University in Japan indicated AHCC improved the life expectancy of patients who received the supplement after undergoing surgery for liver cancer, perhaps due to increased NK cell function.53
Botanicals and Plant-Derived Compounds
The plant world is rife with immune-boosting botanicals and plant-derived compounds. Echinacea is one such botanical that has been touted for its ability to improve a person's odds against beating the common cold. Research surrounding this botanical indicates it improves immune function. A study conducted at the University of Alberta in Canada indicated that rats given an oral preparation of echinacea twice daily for four days exhibited macrophage activity and an increase in TNF-alpha.54
A study out of Southwest College in Arizona compared the immunostimulatory effects of two echinacea species--Echinacea purpurea (E. purpurea) and Echinacea angustifolia (E. angustifolia)--with the immune-enhancing properties of larch arabinogalactan, extracted from Larix occidentalis. Researchers administered various combinations of the extracts to 48 volunteers for four weeks. Results indicated E. purpurea plus E. angustifolia, as well as both echinacea extracts plus the larch arabinogalactan extract, increased production of complement properdin, which is an indicator of immune system stimulation.55
Contrary to these results, researchers at the University of Idaho in Moscow found no evidence of immunostimulatory activity from echinacea. During initial testing, researchers administered the herb to female rats and found no increase in NK cell or T-cell activity.56
Spirulina, a blue-green algae, has immune-enhancing properties for which it has been studied as a chemopreventive agent. Researchers from the Osaka Medical Center for Cancer and Cardiovascular Diseases in Japan administered a hot water extract of Spirulina platensis to subjects and found it enhanced NK cell function.57 In addition, a research review conducted by Calipatria, Calif.-based Earthrise Nutritionals Inc. indicated spirulina may protect against certain forms of cancer because of its effect on the immune system, as well as its ability to repair DNA and protect against free radical damage.58
The aloe plant may also offer an extract that is helpful for immune function. Acemannan, a major carbohydrate fraction of Aloe vera gel, is known for activating immune response, and for its antiviral and anti-tumor activities, according to researchers from Chungbuk National University in South Korea. They studied acemannan's effects on dendritic cells, which are important for the initiation of primary immune response. Acemannan was able to promote the maturation process of these cells in vitro.59
As acemannan is derived from aloe, phytosterols and phytosterolins can be extracted from various plants. These compounds are suspected to inhibit cancer development because of their immune-balancing properties, according to a research review conducted by Patrick J. Bouic, Ph.D., head of immunology at the University of Stellenbosch in Cape Town, South Africa. Specifically, phytosterols and phytosterolins promote lymphocyte activity.60
According to Bouic's research, a proprietary sterols/sterolins mixture (as Moducare™, manufactured by Eugene, Ore.-based EPI Moducare) increased interferon-gamma, which improved the "fighting power" of immune cells. This action is important in the prevention of cancer, according to Bouic. "The sterols/sterolins increase the release of cytokines from immune cells," he explained. "These same cytokines are responsible for making sure that the immune system is maintained in a balanced mode. ... The cytokines that activate the killer cells are responsible for 'neutralizing' other cytokines that promote the functioning of the cells making the antibodies."
Keeping the immune system balanced is important for reducing the occurrence of allergies, autoimmune conditions and viral infections, according to Bouic. "The sterols/sterolins merely provide a safety mechanism by making sure that the right factors are secreted and therefore ensuring that we are always balanced immunologically," he added.
Another plant-derived immunostimulant comes from garlic, which is popular among consumers. According to NMI, 15.4 percent of the general population takes garlic supplements while 25.5 percent of immune sufferers take them.
Researchers from West Virginia University in Morgantown conducted a research review to determine the mechanism of action behind garlic's ability to inhibit tumor growth, which they hypothesized was most likely due to immune stimulation. In comparing garlic to bacillus Calmette--Guerin (an approved immunotherapy for human bladder cancer), researchers noted numerous similarities. Both are known to stimulate growth of lymphocytes and macrophages, induce the infiltration of these cells into transplanted tumors, increase spleen size, and stimulate the release of interleukin-2, TNF-alpha and interferon-gamma, as well as enhance NK cell and cytotoxic T-cell activity.61
Animal research out of Healthcare Research Institute in Hiroshima, Japan, indicated aged garlic extract also enhances immune function. In a series of experiments, researchers learned the extract decreased antigen-specific ear swelling, increased NK cell activities of spleen cells and prevented a decrease in spleen weight. Researchers concluded aged garlic extract may be a promising candidate as an immune modifier, which maintains the homeostasis of immune function, although further studies are warranted to determine for which conditions it is most beneficial.62
While many compounds are isolated from plants and studied for their individual effects, some are studied in their entirety. Flaxseed, for example, has been studied in the realm of women's health--specifically for preventing osteoporosis--and is thought to act on immune health. Flaxseed has many active constituents, including alpha linoleic acid (ALA), plant lignans and antioxidants.
"Essential fatty acids from fish and flax oil are potent immune enhancers, as well as powerful anti-inflammatory agents," wrote Lorna R. Vanderhaeghe and Bouic in The Immune System Cure (Kensington Publishing Corp., 1999). They also noted that the lignans found in flaxseed are known for their anti-cancer effects, as well as anti-fungal, anti-bacterial and antiviral properties.
A research review out of the Sky Park Wellness Center in Irvine, Calif., indicated dietary supplementation with flaxseed and flaxseed oil, as well as fish oil, could significantly reduce cytokine production while at the same time increasing calcium absorption, bone calcium and bone density in postmenopausal women. According to the review, the rapid rate of postmenopausal bone loss is mediated by interleukin-1, interleukin-6 and TNF-alpha. "Possibilities may exist for the therapeutic use of the omega-3 fatty acids, as supplements or in the diet, to blunt the increase of the inflammatory bone-resorbing cytokines produced in the early postmenopausal years, in order to slow the rapid rate of postmenopausal bone loss," the review's authors wrote.63
Another EFA, conjugated linoleic acid (CLA), is suspected to have immune-stimulating effects, according to a presentation given at a National Institutes of Health workshop in May 2002--Perspectives on Conjugated Linoleic Acid: Current Status and Future Directions. A 13-week human trial demonstrated supplementation with CLA (as Clarinol™, manufactured by Channahon, Ill.-based Loders Croklaan) stimulated immune response in humans by increasing the presence of virus-specific antibodies. Using the hepatitis B vaccination as an infection model, 75 human subjects were divided into three treatment groups: one control group and two CLA groups. The two CLA groups received two different ratios of the naturally occurring isomers c9, t11 and t10, c12; one group at a ratio of 50-to-50 and the other group at a ratio of 80-to-20. Those who received CLA with equal (50-to-50) concentrations of the active isomers performed significantly better than those in the control group or the 80-to-20 experimental group. At the conclusion of the study, the antibody level in those who received CLA with c9, t11 and t10, c12 in a 50-to-50 ratio was twice as high as those who received CLA with those isomers in an 80-to-20 ratio or no CLA at all.
Probiotics, which are "friendly" bacteria that live in the human intestinal tract, are most commonly associated with digestive health, although they are thought to promote immune health as well. In particular, probiotic supplements may increase NK cell activity.
Researchers at Massey University in New Zealand suggested probiotic supplementation would be especially useful among the elderly, as the aging process can lead to declined cellular immunity. During a three-stage dietary supplement trial, 30 healthy elderly volunteers consumed low-fat milk for three weeks before and after either a low- or typical-dose regimen with Bifidobacterium lactis (B. lactis) HN019. During the probiotic regimen, subjects exhibited increases in the proportions of total, helper and activated T-cells and NK cells.64 The same group of researchers conducted a separate study on elderly volunteers and learned that supplementation with Lactobacillus rhamnosus (L. rhamnosus) also had a positive effect on lymphocyte activity.65
Similar results were reported by researchers at the National University of Taiwan. They involved 52 healthy middle-aged and elderly volunteers, who received L. rhamnosus HN001. After supplementation with the probiotic in low-fat milk and lactose-hydrolyzed low-fat milk for three weeks, NK cell activity increased by 71 percent and 147 percent, respectively.66
Oral administration of Lactobacillus casei Shirota can also enhance immunity by stimulating NK cell activity and the production of helper T-cells, which repress the production of IgE antibodies, according to researchers at Yakult Central Institute for Microbiological Research in Tokyo.67
Naturally occurring antibodies are also being studied for their immunoregulatory effects when taken as supplements. Because human immunoglobulin is unsuitable for supplementation, purified bovine antibodies are commonly used in commercial preparations.
Research conducted with natural bovine IgG in 1992 demonstrated the antibody was able to neutralize common pathogens, including E. coli and Cryptosporidia.68 Animal research published this year indicated supplementation with bovine serum may be able to improve immune function and fight off opportunistic infection by bacteria. Calves that were immuno-compromised due to Cryptosporidium parvum infection were treated orally with natural bovine immunoglobin (as ImmunoLin™, manufactured by Ames, Iowa-based Proliant Inc.), which was found to enhance the animals' recovery from infection.69
The immunoglobins found in bovine colostrum are known for providing the calf that receives them with the mother's innate protection against microbial infection, according to researchers at the Agricultural Research Centre of Finland. In addition, immunizing cows with pathogens or their antigens can increase colostrum's concentration of specific antibodies against pathogens, such as rotavirus, Shigella flexneri, Escherichia coli, Clostridium difficile, Streptococcus mutans, Cryptosporidium parvum and Helicobacter pylori.70 The same researchers reviewed the characteristics of bovine antibodies and the complement system for use in health-promoting functional foods. They concluded, "Cow's colostrum and milk contain virtually all compounds of bovine cellular and humoral immune defense, including antibodies and complement proteins. ... The main limitation of milk antibodies in human use is that they are derived from a foreign species and can thus be used only against oral and gastrointestinal pathogens or for topical applications. In order to overcome this limitation, it may be possible in the future to produce human antibodies and complement proteins in transgenic cows."71
The immune system, which consists of humoral and cellular elements, must perform at optimal levels to prevent invading antigens from taking hold and causing illness. Several extrinsic factors (i.e., stress, anxiety and depression) can tax the immune system and allow opportunistic invaders to settle in and cause illness. For these reasons, nutrition is imperative to maintaining a healthy immune system, especially during times of extrinsic stress, in order to ensure health and wellness. The solution may lie within the natural products industry; several micronutrients are required for keeping the immune system working properly, and numerous botanical and nutritional supplements can be used to boost both cellular and humoral immunity.
Editor's notes: Some content for this story provided by Intramedicine (www.intramedicine.com).