The Road to Immune Health

Link: Research in the Realm of Immune Function

The high profile of auto-immune diseases such as AIDS and concern about bioterrorism are leading consumers to seek natural ways to boost their immune systems.

The human immune system is a sophisticated network of organs, blood cells and specialized tissues that protect the body from foreign substances such as bacteria, viruses, fungi and parasites. The immune system is a highly specialized front-line of defense that identifies, remembers, attacks and destroys disease-causing invaders or infected cells. Essentially, the immune system is the body's means of surveillance, intended to protect the body from disease by searching and destroying any health-damaging agents. The immune system also defends against invaders from within the body, which can be the most threatening of all.

To understand the importance of the immune system and how dietary supplements can strengthen or stimulate it, one first must know a bit about how it works. The immune system is an assortment of specialized cells that protect the body in several different ways. These specialized cells occupy every part of the body, from the skin, eyes and lungs to the lining of the internal organs. The most abundant concentration of immune cells is found in the lining of the gastrointestinal (GI) tract, which is continually exposed to microorganisms and toxins found in daily diets.

There are several types of immune cells, each possessing specific duties and characteristics. Some travel through the body, killing foreign substances as they find them. Others patrol the GI tract lining and blood vessels, safeguarding particular organs. The lymphatic system, which includes the lymph nodes, the spleen, bone marrow and thymus gland, produces these cells and transports them throughout the body. Lymph nodes and the spleen serve as filters designed to keep harmful organisms out of the bloodstream.

Most immune cells are produced in bone marrow, the thymus or the spleen. Red blood cells originate within bone marrow from stem cells and, once fully developed, will travel through the lymphatic system looking for foreign invaders. T-cells are made in the thymus, and most B-cells are found in the bone marrow. T-cells and B-cells are also known as lymphocytes and have the ability to recognize antigens (foreign particles that stimulate the immune system into forming an antibody). Both T-cells and B-cells are the core of adaptive immunity, as well as natural killer (NK) cells, which seek out tumor or virally infected cells. NK cells offer another line of defense against invading microorganisms, parasites, viruses, bacteria and fungi.

T-cells respond to the body's own cells that have changed in response to a viral invasion or cellular mutation. There are three types of T-cells: helper T-cells, cytotoxic T-cells and suppressor T-cells. Helper T-cells secrete types of interleukin to stimulate the activity of the cytotoxic T-cells. These cells recognize specific antigens and inject cytotoxic granules into the targeted cell, which eventually kill the cells. Cytotoxic T-cells also attract macrophages to clean up the area under attack. Suppressor T-cells have the job of shutting down the activity of the immune system after the infection is cleared.

B-cells are unlike other cells in the body and are responsible for alerting other immune cells of foreign substances that may be harming the body. If B-cells encounter an antigen, they will "tag" the invader with proteins called antibodies (or immunoglobulins).

There are five classes of immunoglobulins, including IgA (found in the gut), IgE (linked to hypoallergenic responses) and IgG (the most abundant and active type). These immunoglobulins are found in colostrum, a pre-milk fluid produced in female mammals in the mammary glands just before they give birth. These antibodies provide proteins, growth factors and other compounds that help jump-start an infant's immune system. In the natural products industry, bovine colostrum delivers substances such as polyproline-rich peptides and high amounts of Ig compounds, particularly IgA. A research review of bovine colostrum (Br J Nutr, 84 Suppl 1:S135-46, 2000) provides additional evidence that the immunoglobulins from colostrum provide major antimicrobial protection against microbial infections and can balance microbial flora. Other ingredients, such as bovine serum (available as ImmunoLin™ from Proliant Health), also deliver a high concentration of immunoglobulins, immunoregulators and growth factors, without fat or lactose. Proliant noted that bovine serum offers a higher concentration of immunoglobulin and bioactive peptides, which are more easily absorbed by the digestive tract.

Immunity Rundown

There are two types of immunity that protect the innate response and adaptive response. Innate immunity is present at birth and provides the first barrier against microorganisms. The skin, mucus secretions and the acidity of the stomach are examples of innate immunity and act as barriers, shielding vulnerable tissues from unwanted germs. These mucosal surfaces contain types of immunoglobulins (primarily IgA), which function as antibodies to help determine which non-self organisms are pathogenic and which are innocuous.

Phagocytes may also release pyrogens to fight off infection. These cells increase the body's temperature, speeding up metabolism and the healing response. Should foreign matter actually find its way into the body, the immune system may destroy the matter using a process called phagocytosis, a process which eats and digests the unfamiliar matter. The cells involved in phagocytosis, called phagocytes, include granulocytes and macrophages.

Adaptive immunity is the second barrier against infection. It is acquired later in life, for example, after an immunization or after fighting off an infection. The adaptive immune system retains a memory of all the invaders it has faced--measles and chicken pox being primary examples. However, some bugs, such as viruses that cause the common cold, disguise themselves and must be fought off time and again by the immune system.

Thanks to antibodies, a specific protein produced in the immune system, the body is capable of destroying antigens. If a specific antigen invades the body, an antibody is produced to destroy that particular antigen and only that antigen. After initial contact with an antigen, this adaptive branch of the immune system records the attack and produces an antibody--allowing the body to acquire the necessary data to defend itself against another attack from the same source should there ever be one. If a different type of antigen is presented, the same process occurs, whereby an antibody specific to that antigen will be created.

Boosting Immunity Through Vitamins and Minerals

The idea of enhancing individual immunity has led many consumers to vitamins, minerals and herbs that may strengthen or modulate the immune system naturally. In addition, a growing number of autoimmune diseases such as cancer and acquired immunodeficiency syndrome (AIDS) have helped keep the field of immunology at the forefront of international research and public attention.

According to a Natural Marketing Institute (NMI) survey conducted by the National Family Opinion, approximately 4.2 percent of the general population actively managed immune problems in 2001. Fifty-six percent of these individuals noted that they turned to vitamins and minerals for overall health and wellness, and 42 percent used them to treat specific health issues. Vitamins were noted as the primary supplement choice for managing immune problems at 90 percent, minerals at 73.5 percent and herbal supplements at 63.8 percent; however, consumers were likely to purchase a variety of supplements, including vitamins C and E, calcium, antioxidants and garlic.

Vitamins and minerals are necessary in maintaining a healthy immune system. Within the body, vitamins and minerals act as enzymes and coenzymes (which work to facilitate other reactions) for every function of the body. Vitamin D, for example, has been shown to either prevent or markedly suppress autoimmune disease by stimulating TGFbeta-1 and interleukin 4 production (which can suppress inflammatory T-cell activity) (FASEB J, 15, 14:2579-85, 2001). Additionally, vitamin E has been studied for its effect on the thymus and white blood cells, which may suffer from oxidative stress and viral illnesses such as AIDS and hepatitis. Vitamin E supplementation has also been said to improve cell-mediated immunity, enhance digestion in cells and increase resistance to infection, noted Lorne R. Vanderhaeghe in Healthy Immunity (Macmillan Canada, 2001). When combined with vitamin C, it can work cooperatively to increase the number of T-cells and reduce inflammation. It also works synergistically with coenzyme Q10 (CoQ10).

Antioxidants have also gained a reputation for supporting the immune system. With their ability to scavenge free radicals, antioxidants such as vitamins A, B and C provide protection against viral infections. Other antioxidants include CoQ10, lipoic acid, carotenoids and bioflavonoids.

Vitamin C has been shown to strengthen connective tissue and neutralize toxic substances that are released by phagocytes. A study conducted at the University of Witwatersrand Medical School, South Africa, further confirmed vitamin C's immune benefits. Researchers at the university gave 25 patients 1 g/d of vitamin C for 75 days. Results revealed that IgA and IgM antibodies increased, even though the placebo group showed no immune-enhancing effects (Scand J Infect Dis, 26: 4-5, 1994). Another study published in Immunopharmacology and Immunotoxicology (19, 3:291-312, 1997) found that individuals with low to inadequate NK cell and B-cell activity could boost NK cell activity tenfold and improve B-cell function by consuming vitamin C at levels of 60mg/kg of body weight.

Promising research on vitamin A continues to show that the nutrient may have immunomodulatory effects. It is already used to assist in human growth and tissue differentiation, as well as assisting in differentiation of epithelial cells (the cells that form the body's skin, mucous membranes and blood vessel walls). One study comparing patients with common variable immunodeficiency (CVI) with healthy controls demonstrated that the majority of CVI patients had low vitamin A levels, and that supplementation of vitamin A in these patients resulted in increased immune function (Eur J Clin Invest 30, 3:252-9, 2000) .

The B vitamins act as co-enzymes that help the body metabolize food into energy, synthesize antibodies for the immune system and provide daily support. Perhaps one of the most important nutrients for supporting immune function is vitamin B6, which is needed to make antibodies and slow tumor growth. "Immune enhancement relies upon adequate vitamin B6," wrote Vanderhaeghe in The Immune System Cure (Kensington Publishing, 1999). "Without it, the thymus will shrink and a reduction in the amount of thymulin will result. T-cell activity will diminish along with B-cells and antibodies."

In one study, researchers found that repletion of the vitamin can influence tumor growth and disease processes; however, megadoses do not produce benefits beyond those observed with moderate supplementation (Nutr Rev, 51, 8:217-2, 1993). It is also important to note that vitamin B6 should be taken in conjunction with the other B vitamins to maximize the vitamins' synergies.

Minerals also play an important role in immune health. As part of the antioxidant enzyme glutathione peroxidase, selenium may protect white blood cells from free radical damage and also appears to increase antibody production, as well as accelerate production of leukocytes. Copper deficiency may also lead to reduced resistance to infection. There is speculation that the ratio of zinc to copper may be crucial in immune function. In a plethora of studies, zinc proved to have the most specific effect on the immune system. According to researchers, zinc plays a unique role in T-cell mediated response and, when combined with thymic hormones, it forms a biologically active thymic hormone molecule (Proc Natl Acad Sci, 82:7035, 1985). Additional research further supports that zinc supplementation could increase immune function (Am J Clin Nutr, 34:88-93, 1981) (Fed Proc, 45:1474-9, 1986). "Zinc is the only mineral that has been found to play a key role in every component of the body's immune system," said Max R. Motyka, M.S.R., Ph.D., of Albion Advanced Nutrition. "The immunologic mechanisms in which zinc modulates against our susceptibility to infection have been studied for several decades. Its effects are across the board, impacting defense systems from skin barrier to gene regulation in infection fighting lymphocytes."

Zinc has recently been touted as preventing and treating the common cold, although evidence proving this theory is still questionable. Recently, researchers in a randomized, double blind, placebo-controlled trial evaluated the efficacy of zinc sulfate nasal spray for reducing the duration and severity of upper respiratory infections in 160 subjects (Am J Med, 11, 2:103-8, 2001). Researchers discovered that while zinc reduced the total and nasal symptoms on the first day of treatment, it did not have any effect on the length of infection.

Still, researchers note that zinc supplementation is necessary for a weak immune system since it improves antioxidant functions, stabilizes membranes and plays a key role in the activity of zinc metalloenzymes, noted Debasis Bagchi of InterHealth, manufacturer of OptiZinc™. "Zinc deficiency causes a reduction in T-cells, natural killer cells and thymic hormone," added Vanderhaeghe. "Supplementation with zinc increases the ability of macrophages to digest invaders, dead cells and other debris, and enhances the ability of the immune system to eliminate bacteria."

Low levels of selenium can make the body susceptible to cancer, viruses and free radical damage. Also considered an antioxidant, this mineral is responsible for creating an enzyme called glutathione peroxidase, which is necessary for detoxifying the body from environmental toxins. One study investigated the effects of supplemented selenium (through foods naturally high or low in the mineral) of 11 healthy men (Biol Trace Elem Res, 81, 3:189-213, 2001). After 120 days, participants who were given high amounts of selenium experienced a decrease in white blood cell counts, while the low-selenium group had an increase, resulting primarily from changes in granulocytes. Increases in cytotoxic T-lymphocytes and activated T-cells in the high-dose selenium group were also noted. Results from the study indicated that the immune-enhancing properties of selenium are a result of improved activation and proliferation of B-lymphocytes and enhanced T-cell function. Another study provided additional evidence that the combination of selenium and zinc was important to immune function in the elderly (J Nutr, 131,10: 2677-84, 2001).

Mushrooms for Health

The immune benefits of medicinal mushrooms and related components have become increasingly interesting to consumers looking to manage their health. Ingredients such as reishi, shiitake, maitake, AHCC, and MGN-3 have caught the media's attention--mainly on account of the studies conducted on these supplements.

Reishi and shiitake have been consumed in China for more than 3,000 years due to their ability to improve general health. In Asia, reishi is considered to be the most effective of all medicinal mushrooms to strengthen the body, and shiitake is not only used in cooking but as a remedy for upper respiratory diseases, poor blood circulation, liver trouble and overall weakness. Because these mushrooms have an active constituent called beta-glucan, they are especially important to the immune system when fighting cancer cells and countering the effects of aging. Maitake D-fraction, such as a patented formula called Grifron-Pro Maitake D-fraction from Maitake Products, appears to have the most active form of beta-glucan when compared to other mushrooms (Food Reviews Int, 11,1: 135-149, 1995). Because the chemical structure of maitake's polysaccharide compound is slightly different than the beta-glucans found in other medicinal mushrooms, it is recognized by researchers as the most effective active agent stimulating cellular immune responses. One in vitro study showed that beta-glucan made breast cancer cells more susceptible to immunotherapeutic targeting by NK cells, in addition to promoting stronger overall NK activity (J Immun, 159:599-605, 1997).

AHCC (Active Hexose Correlated Compound), a monosaccharide produced from a shiitake hybrid in a rice bran extract, has been heavily touted as of late. "In the case of AHCC, there is an unusual combination of mainstream acceptance by the medical profession and the general public," said Dan Kenner, Ph.D., Lac. "AHCC is close to being considered a mainstream cancer therapy in Japan and its acceptance is rapidly gaining in other countries."

The combined effects of medicinal mushrooms such as those found in AHHC seem to be stronger than individual mushrooms. According to the company American Biosciences, AHCC stimulates NK cell activity, providing a stronger first-line defense against cancer. It has been shown to increase interferon levels, increase formation of tumor necrosis factor (TNF) and increase the number of explosive granules in each NK cell. At the 1998 European Society for Surgical Research, a study was presented that examined 70 patients with pathologically confirmed liver cancer who took 3 g/d of AHCC following surgery, compared to 82 patients with surgery only. As of September 1999, 49 percent of the AHCC group had recurrences, compared to 67 percent of the control group.

Several other studies have shown that AHCC activates the production of cytokines (chemical messengers that communicate between cells) and that AHCC increases NK cell activity by increasing the number of granules they contain (AHCC Research Association 8th Symposium, 2000) (7th Annual Conference on Clinical Immunology, 1992).

A related complex is a patented product from Lane Labs called MGN-3, a natural substance that has been shown to strengthen the immune system's NK cells. The product is made from the outer shell of rice bran and treated and hydrolyzed under controlled conditions with enzymes from the shiitake mushroom. Research also indicates that MGN-3 does not necessarily increase the number of NK cells, but it does increase existing cell's potency, said I. William Lane, Ph.D., in Immune Power (Avery Publishing, 1999). According to one study, MGN-3 influenced NK cells to double or triple their activity (J of Immuno, 11: 23-28, 1995). "The fact that MGN-3 affect the NK cells' activity rather than their numbers makes it a true biological response modifier, or BRM--a nontoxic substance that has measurable effects on biological responses, such as those of the immune system," Lane said.

Immune Building Through Sterols, Soy and Spices

"[The immune system is a] highly evolved system that has all the properties to defeat disease and keep us healthy," Vanderhaeghe said. "All we have to do is provide it with the appropriate tools to do its job--good nutrition, food supplements, stress reducers and exercise."

Changes in an individual's diet can be an impressive first step in strengthening the immune system. A varied diet of organic fruits and vegetables, lean fish, meats and poultry, whole grains and good fats can provide some of the basic requirements of vitamins and minerals. Foods rich in phytosterols such as sterol esters and sterolins are also recognized as immune-friendly nutrients. Found abundantly in plant materials, shellfish, and unprocessed nuts and seeds, sterols have been studied extensively for their immune-modulating benefits. A review of plant sterol and sterolin studies revealed that phytosterols target specific T-helper lymphocytes, helping to normalize T-lymphocyte and NK cell activity (Altern Med Rev, 4, 3:170-7, 1997). One study in particular showed that sterols and sterolins had a significant effect on human T-cells. The experiment found that a 100:1 sterol/sterolin mixture could be a potent immunomodulator for the treatment and restoration of immune dysfunctions (Int J Immun, 18,12: 693-700, 1996).

Scientists report that nutrition plays a supporting role in immune function and that adequate intake of protein and calories are necessary in maintaining the body's defenses. Malnutrition and poor diet can rob the body of its defense capabilities, depleting white blood cells and important immune system proteins.

Other preventive measures include limiting sugar and alcohol consumption. It has been long understood that forms of sugar may interfere with the ability to destroy bacteria (Am J Clin Nutr, 26:1180, 1973) and the body's production of antibodies. High intake of alcohol can also disrupt a variety of immune defenses (Crit Rev Tox, 25, 4:347-67, 1995) (Alcohol Clin Exp Res, 22:216-9s, 1998).

Soy products have entered the limelight as an important part of an immune building diet. Saponins, one component of soy, may lower cholesterol and prevent cancer cells from multiplying. Isoflavones, folic acid, calcium, magnesium, zinc and lignans are also found abundantly in soy products, as well as protease inhibitors, which suppress and slow the spread of cancer cells. The isoflavone genistein has also been recently studied for its effects on immune response. A study held at the Department of Pharmacology and Toxicology, Virginia Commonwealth University (J Nutr, 131,12: 3251-58, 2001), examined the relationship between genistein and immune responses. Results indicated that when innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell activity was observed. Furthermore, genistein enhanced immune resistance, which may be related to the increase in activity of cytotoxic T cells and NK cells.

Garlic has also gained attention in its ability to aid immune repair. While it has been used for its medicinal properties for thousands of years, investigations into its mode of action are still recent. According to a recent review, garlic has a wide spectrum of actions; not only is it antibacterial, antiviral, antifungal and antiprotozoal, but it also has beneficial effects on the cardiovascular and immune systems (Appl Microbiol Biotechnol, 57, 3:282-6, 2001).

The effects of aged garlic extract (AGE) look promising as well. In one study, researchers found that ear swelling and toxic cell reproduction in immunoglobulin-mediated mice decreased and, consequently, NK cells and killer activities of spleen cells were increased (J Nutr, 131, 3s:1075s-9s, 2001)."AGE could be a promising candidate as an immune modifier," wrote the researchers from the Healthcare Research Institute at Hiroshima, Japan. However, "future studies are warranted to determine when it is most beneficial."

Another culinary spice also offers general immune support--oil of oregano. Known as a spice with significant immune and germ-killing power, wild Mediterranean oregano has been extensively studied for its potent germicidal properties. For example, researchers at Georgetown University found that a blend of wild oregano oils (known as Oreganol P73 available from North American Herb & Spice) killed Candida albicans, a stubborn human pathogen that is involved with bladder infections, vaginal disorders and post surgical infections. And research at Cornell University found that of all natural substances evaluated, oregano was one of the few that killed all germs against which it was tested--some 30 different germs. According to Cass Ingram, D.O., wild oregano oil is the potent lymphatic tonic that can increase lymph flow, whether it is used topically or internally.

Antimicrobial properties are also a benefit of olive leaf extracted from the leaves of the Mediterranean-found olive tree. Oleuropein, the primary active component in green olives is a bitter, phenolic glycoside found throughout the olive tree. It is believed to be the major factor in olive leaf's antimicrobial properties. In addition to its historical use in malaria patients, olive leaf had been shown to cease growth of a variety of viruses and bacteria, including herpes 1 and 2, S. aureus and Bacillus cereus.

Finding the Right Combination

Much like the way one person catches the flu and another person does not, not every product is right for everyone. Individuals have varying degrees of immunity because of a flexible immune system, which changes with a person's external environment.

With everything that is out there, retailers and consumers should be wary of products that do not provide research on how the product responds to the immune system. "Because of its complexity, drugs--whether they are herbs or pharmaceuticals--that simply 'boost' the immune system may do more harm than good," wrote Lane. "It is essential that any product that modulates immune-system function has solid scientific evidence behind it, as well as clinical trials."

Immunologist Mamdooh Ghoneum, Ph.D., added, "We see immune therapies, both natural and synthetic, that work well for a certain period of time, but then their effectiveness wanes, even though the regular dosage is continued." He also noted that a quality product is one that is well researched and includes a trail of quantitative animal and in vitro studies.

Research in the Realm of Immune Function

Chlorophyll May Help Immunity

Aphanizomenon flos-aquae (Aph. flos-aquae) may be able to strengthen the immune system and lower cholesterol in humans because of its chlorophyll content, according to researchers at Harvard's Pediatric Gastroenterology and Nutrition Program and Cell Tech, by helping certain immune cells perform their surveillance function better.

Jensen GS et al. "Consumption of Aphanizomenon flos-aquae has rapid effects on the circulation and function of immune cells in humans." JANA. 2, 3: 50-8, 2001.

Echinacea Effective in Treating Colds

Echinacea was deemed effective and well-tolerated for treating symptoms associated with colds and flu by physicians at the Company Medical Service in Madaus AG, Cologne, Germany.

Schulten B et al. "Efficacy of Echinacea purpurea in patients with a common cold: a placebo-controlled, randomized, double blind clinical trial." Arzneimittel forschung. 51,7: 563-8, 2001.

Echinacea May Be Safe for Pregnancy

Echinacea supplementation during pregnancy may not affect the developing fetus, according to researchers at The Hospital for Sick Children in Toronto. Despite a lack of statistical risk for using echinacea, pregnant women taking this herb may need to exercise caution.

Gallo M et al. "Pregnancy outcome following gestational exposure to echinacea: a prospective controlled study." Arch Intern Med. 160,20: 3141-3, 2000.

Maitake Mushroom Preparation Has Cytotoxic Effect

A bioactive beta-glucan preparation from maitake mushroom may have a cytotoxic effect on prostatic cancer cells, leading to apoptosis (programmed cell death). According to researchers at the Department of Urology, New York Medical College, almost complete cell death was attained in 24 hours with treatment of Grifron Pro D-fraction greater than 480 mcg/mL.

Fullerton SA et al. "Induction of apoptosis in human prostatic cancer cells with beta-glucan (Maitake mushroom polysaccharide)." Mol Urol. 4,1: 7-13, 2000.

Phorbol Ester May Assist HIV Patients

Prostratin, a phorbol ester, may be effective in combination with highly active antiretroviral therapy (HAART) for HIV, according to researchers from Thomas Jefferson University, Philadelphia. Research results indicated that prostratin has the ability to block HIV-1 infection and reduce viral infectivity of treated host cells.

Kulkosky J et al. "Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART." Blood. 98,10: 3006-15, 2001.

Right Combo Improves Immunity

The combination of L-arginine, omega-3 fatty acids and yeast RNA were shown to improve post-operative recovery from heart surgery by researchers from the University of Amsterdam. Patients who took this combo at least five days before undergoing coronary artery bypass surgery experienced a stronger immune response, fewer postoperative infections and better renal function compared to those who had received placebo.

Tepaske R et al. "Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomized placebo-controlled trial." Lancet. 358,9283: 696-701, 2001.

Shiitake Mushroom Treated Rice Bran May Offer Therapy for HIV Patients

MGN-3, which is a patented constituent of rice bran modified with Shiitake mushroom enzymes, may offer therapeutic effects for HIV. Researchers from Charles Drew University and the University of California, Los Angeles, found that MGN-3 could suppress cancer growth during a 16-hour incubation period.

92nd Annual American Academy of Cancer Research, 2001.

Vitamin D May Inhibit TB Growth

Vitamin D may still play an important role in tuberculosis by enhancing the ability of human monocytes to restrict the growth of intracellular mycobacterium tuberculosis (TB), according to researchers at Case Western Reserve University, Cleveland. Researchers concluded that there was insufficient evidence to recommend routine vitamin D supplements for tuberculosis.

Wilkinson RJ et al. "Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study." Lancet. 355,9204:618-21, 2000.

Additional reporting by Kim Schoenhals.

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