From February 1999 Issue of Nutrition Science News
By Marcia Zimmerman, C.N.
The immune system is the body's ultimate defense against infectious agents such as bacteria and viruses. It also protects against genetic mistakes made in cellular replication that result in tumor or cancer growth. The immune system is complex, containing many interacting blood cells, proteins and chemicals. A healthy immune system contains elements that are in balance with one another. In a compromised immune system, the components are unbalanced and unable to protect the body against harmful agents or processes.
Western medical doctors seek to bolster immune system activity by providing either chemotherapeutic agents such as methotrexate, an antimetabolite, that arrest aberrant cellular growth, or bioengineered molecules similar to elements of our own immune complex, such as the alpha-interferon used for genital warts, that will fight for us. The modern medicine bag also contains vaccines, which may contain either dead or weakened bacteria or viruses or other materials such as inactive toxins. Upon injection, the vaccine, which is typically not strong enough to cause an infection, stimulates the body's immune system to produce antibodies against the perceived pathogen. Despite their overall saftey, vaccines and other methods can sometimes produce side effects and upset the immune system's balance.
In contrast, traditional medical practitioners use botanicals and other natural substances to stimulate or potentiate the body's own defense mechanisms rather than substitute for them. This way the body's natural balance is preserved, and side effects are either not present or substantially reduced. Although both vaccines and botanicals elicit an immune response, vaccines boost the body's response to a specific pathogen whereas botanicals tend to enhance overall immunity. Immune-potentiating botanicals are also used to increase the effectiveness of drugs and reduce side effects. The Chinese call this Fu Zheng therapy, which means to support the body's natural balance.
Many of the following botanicalsshiitake, maitake, licorice, echinacea, ligustrum and astragalusowe their effects to a group of polysaccharides. These complex sugars have the ability to activate macrophages, which are white blood cells that process antigens and present them to T cells (lymphoid cells that migrate from the bone to the thymus). These polysaccharides also stimulate T cell formation and differentiation, as well as activate a group of more than 25 blood proteins that play a vital role in the body's immune defenses.
Medicinal MushroomsAn Umbrella of Protection
An estimated 100,000 varieties of mushrooms exist; some 700 are used for food, and about 50 appear to have medicinal value. For centuries, mushrooms have been used in Asia both as food and as medicine. Two of the more popular varieties of edible, medicinal mushrooms are shiitake and maitake.
Shiitake mushrooms (Lentinus edodes) are highly prized, both for their culinary use and as immune-potentiating agents. Their most studied active principle, lentinan, is a polysaccharide composed of beta-1,3-glucans with beta-1,6-glucan side chains. [1, 2] Lentinan stimulates the antioxidant activity of both superoxide dismutase (SOD) and macrophages in vitro, especially when levels of these detoxification agents are low. [1, 3 ]Other active principles also occur in shiitake, namely KS-2, a glycoprotein that is isolated in what is called a D-fraction from shiitake mycelia and in RNA isolated from spores. The former stimulates interferon production in animal models when administered orally. Interferon, produced by white blood cells, prevents viral protein synthesis. The RNA fraction appears to increase protection against influenza in mice, at least when administered intravenously. [4, 5]
It is wrong to focus exclusively on individual agents, however, since multiple active principles appear to be involved in the effectiveness of shiitake. This efficacy has been borne out by its long history of use in traditional medicine. Although scientific investigation must focus on a single isolated compound to pinpoint specific activity, using the whole herb takes advantage of shiitake's multiple benefits.
Maitake mushrooms (Grifola frondosa), may have medicinal benefits more potent than those of shiitake. This is because maitake's polysaccharides are beta-1,6-glucan with beta-1,3-glucan side chains, which result in a more complex branching structure. Since maitake is a newcomer in the medical field, U.S. studies are just being completed on what components are effective and how they work. [6, 7 ]
The effects of maitake D-fraction on cancer were studied by Hiroaki Nanba, Ph.D., and colleagues from the department of microbial chemistry at Kobe Pharmaceutical University in Japan. An uncontrolled study on mice found maitake to be most effective in inhibiting cancer growth of the breast, lung, liver and prostate. Effectiveness ranged from 73.3 to 45.5 percent reductions in cancer growth. It was also somewhat effective in cases of leukemia (25 percent), stomach cancer (33.3 percent) and bone cancer (0 to 16 percent). Maitake was also effective when combined with chemotherapy (an added 4 to 13 percent benefit).  In fact, maitake reduced the side effects of chemotherapy so it was better tolerated and more effective. This latter effect has been attributed to the fractions named X and ES found in the mycelia of the mushroom. Therefore, in cancer treatment, it was suggested a D-fraction concentrate be combined with mushroom mycelia.
The D-fraction has been found to activate natural killer (NK) cells, macrophages and memory T cells. A second study by the same researchers showed T cells are responsible for maitake's ability to help the body resist cancer metastases. This is because memory T cells help the immune system remember the cells that promoted the original tumor and tag them for destruction before they can promote tumor growth in other parts of the body.  Therefore, maitake is effective not only in reducing cancer tumors but also in preventing their recurrence. Maitake also activates several cytokines, which are proteins produced by white blood cells. The cytokines, namely interleukins 1 and 2 (IL-1 and IL-2), attach to T cell lymphocytes, helping them essentially clone themselves into an army of cells that attack tumor-promoting cells.
|The shiitake mushroom (Lentinus edodes) is both a food source and general immune booster. Astragalus (A. membranaceus) and ligustrum (L. lucidum) often work together to increase T cell activity, an essential step in the body's specific immune response.|
As for the specific effects of the X and ES fractions found in mushrooms, an initial laboratory study on the adaptogenic properties of maitake, and specifically its effects on glucose/insulin metabolism, has just been completed at Georgetown University Medical Center in Washington, D.C. Head researcher Harry Preuss, M.D., announced the promising results of maitake's antihypertensive and antidiabetic effects in animal models at the annual meeting of the American College of Nutrition, held October 1998 in Albuquerque, N.M.  Preuss expects to begin Phase II trials immediately.
As the medicinal effects of shiitake and maitake are more clearly defined, we can better appreciate how highly esteemed these edible mushrooms have been, both in the Asian diet and in traditional medical practice.
Flora for Immune Fortification
Licorice root (Glycyrrhiza glabra, G. uralensis) is one of the oldest recorded remedies. It has been used in Chinese medicine to assist the therapeutic effects of other herbs and to reduce their potential side effects.
Glycyrrhizin, the primary identified active principle in licorice, glycyrrhizin is a triterpene saponin. Triterpene refers to the 30 carbon molecules attached to a compound's chemical structure. Saponins are widely distributed in naturemost saponins are triterpenesand form a frothy, soaplike solution when shaken in water. Glycyrrhizin has a chemical structure similar to that of steroid molecules. Its similarity to steroids may account for its anti-inflammatory action, one of licorice's important effects on immune response.  Hirohiko Akamatsu, M.D., and colleagues from the department of dermatology at Kansai Medical University in Japan, identified the ways in which licorice appears to exert its beneficial effects. Rather than demonstrating steroidal, cortisonelike effects on inflammationreduction of tissue swelling from histamine, increased blood flow and leukocyte infiltration of damaged or infected tissueslicorice root has been shown in in vitro studies to effectively reduce inflammation by mopping up excess free radicals liberated in a free radical burst at the site of inflammation.  Superoxide, hydrogen peroxide and hydroxyl radicals are released during inflammation to disable targeted bacteria and viruses, a beneficial effect that is often overdone. Similar results were obtained in a 1983 study in which licorice root reduced the number of free radicals liberated by macrophages. 
The activity of licorice on the immune system has been described as "nonspecific" by most investigators.  This means licorice stimulates, activates or promotes an immune response in multiple ways. Earlier studies identified several of these effects. For example, researchers found that licorice appears to promote proliferation of B (from the bone) and T cells and stimulate production of interleukin-19, which stimulates T cells.  Licorice also appears to stimulate the production of gamma-interferon by lymphocytes [14, 15] and the differentiation of T3, T4 and T8 cells, specific kinds of activated lymphocytes. [14-16]
Echinacea (Echinacea purpurea, E. angustifolia) contains a polysaccharide fraction that, like licorice's, has anti-inflammatory activity. However, echinacea appears to use a different method that inhibits leukocyte migration to the area of inflammation rather than interrupting the enzymatic activities or free radical burst of the white blood cells. [17, 18] Barbara Müller-Jakic, M.D., and her colleagues at the University of Munich in Germany found that echinacea also inhibits inflammatory prostaglandin formation in both human and animal cell cultures. In this case, the alkamide fraction, a chemically active component of echinacea, was identified as the inhibiting factor. 
Because macrophages are often first to sound the intruder alarm, macrophage activation is one of the most important events in immune resistance. Echinacea polysaccharides are powerful macrophage activators as demonstrated by two studies in the late 1980s. [20, 21] A study completed in 1997 by Darryl See, M.D., and colleagues from the University of California at Irvine Medical Center confirmed these earlier findings in vitro. The study also showed extracts of E. purpurea and Panax ginseng enhanced cellular immune function of peripheral blood mononuclear cells (PBMC), from both normal individuals and patients with depressed cellular immunity. The extracts also increased antibody-dependent cellular cytotoxicity of PMBC from all subject groups. Natural killer cell activity was enhanced in cells taken from these individuals. 
A 1997 study found several fractions containing specific components of echinacea activated macrophages. Roger Burger, Ph.D., from Utah State University in Logan, reported that "the multiplicity of compounds found in the unfractionated extract may provide a greater immune stimulatory capability." Researcher cited upregulation of the interleukins IL-6 and IL-10 and tumor necrosis factor in macrophages obtained from acute-phase infection respondents. These cytokines, in turn, activate T and B lymphocytes to produce antibodies, fight bacteria and viruses, and produce deadly chemicals that destroy a variety of organisms.  Such studies help explain the traditional Native American practice of using the whole echinacea plant.
This brings us to two studies that examined the effects of echinacea against Listeria monocytogenes and Candida albicans. Both organisms occur naturally in the body but cause trouble when the immune system is weakened. One study reported that macrophages were more active and effective after echinacea administration, even when the mice were given cyclosporin, an antibiotic that inhibits macrophage activity.  This study confirmed earlier research reporting the same results in mice. 
Finally, echinacea is reported to be a potent inhibitor of human tumor cells cultivated in the laboratory.  Other research demonstrates that it activates production of lymphokines by lymphocytes, a kind of large phagocytic white blood cell. 
Ligustrum (Ligustrum lucidum) fruit has been used for several centuries in Chinese medicine. Substantial empirical evidence indicates ligustrum possesses immune-modulating effects, including cancer inhibition.  Today, ligustrum is an important herb for immune-system restoration after chemotherapy (as part of Fu Zheng therapy), as are astragalus and shiitake. Him-che Yeung, Ph.D., of the Institute of Chinese Medicine in Los Angeles, suggests that ligustrum increases white blood cell count and shows antitumor and antibacterial effects. 
An in vitro study of human cellular response compared the T cell response of 19 cancer patients with 15 healthy subjects. Researchers found that cells pretreated with ligustrum extract returned to normal more quickly after they had been exposed to chemotherapeutic agents.  They attributed this activity to a nonspecific immune activation by ligustrum.
Astragalus (Astragalus membranaceus) contains biologically active components of two classes, polysaccharides and saponins.  However, the reviewed studies used the whole herb, rather than isolated fractions.
Astragalus and ligustrum are customarily used together in Fu Zheng therapy. One study found increases in the number and activity of phagocytic cells obtained from normal subjects after
pretreatment with the two herbs. These herbs also enhanced the differentiation of T cells into active helper T cells. These, in turn, help other immune cells fight bacteria, viruses, parasites, fungi, toxins and diseased cells. 
Astragalus also reduces autoimmune response (and thus allergy, rheumatoid arthritis and lupus erythematosus), and stimulates B cells and antibody production. Researchers confirmed that astragalus enhances T cell activity and stimulates macrophages, which produce cytokine tumor necrosis factora potent immune weaponand interleukin-6 which mediates acute-phase response. [32 ]At the same time, astragalus suppressed tumor growth and restored immune function compromised by tumor growth. [33 ]These findings confirmed earlier observations.  Both studies were animal in vitro studies.
All the botanicals discussed in this article can be taken to prevent the onset of illness, but they are equally effective during acute illness or in combination with drug therapy. Cell and animal studies are now defining how and why botanicals are effective, research that may someday validate, in Western terms, the rich history of Chinese and European herbal medicine.
Marcia Zimmerman, C.N., is author of The ADD Nutrition Solution: A Drug-Free 30-Day Plan (Henry Holt/Owl Books, 1999).
1. Abel G, et al. Effect of lentinan on pinocytosis in mouse peritoneal macrophages and the murine macrophage cell line C4MØ in vitro. Intl J Immunopharmacol 1986;8(8):919.
2. Kerékgyártó C, et al. Strain differences in the cytotoxic activity and TNF production of murine macrophages stimulated by lentinan. Intl J Immunopharmacol 1996;18(6/7):347.
3. Fehér J, et al. Effect of lentinan on superoxide dismutase enzyme activity in vitro. Immunopharmacol Immunotoxicol 1989;11(1):55.
4. Suzuki F, et al. Antiviral and interferon-inducing activities of a new peptidomannan, KS-2, extracted from culture mycelia of Lentinus edodes. J Antibiot 1979 Dec;32(12):1336.
5. Suzuki M, et al. Antitumor and immunological activity of lentinan in comparison with LPS. Intl J Immunopharmacol 1994;16(5/6):463.
6. Press release. Maitake D-fraction obtained IND for clinical study. 1998 Feb 1.
7. Press release. Georgetown University announced effects of maitake mushroom extract on CVD. 1998 Oct 16.
8. Nanba Hiroaki, et al. Results of non-controlled clinical study for various cancer patients using maitake D-fraction. Explore 1995;6(5):19-21.
9. Nanba, H. Activity of maitake D-fraction to inhibit carcinogenesis and metastasis. Cancer PrevAnn NY Acad Sci, 1995 Sep. 30;768:243-245.
10. Tang W, Eisenbrand G. Chinese drugs of plant origin. Berlin: Springer-Verlag; 191-7, 567-91.
11. Akamatsu H, et al. Mechanism of anti-inflammatory action of glycyrrhizin: effect on neutrophil functions including reactive oxygen species generation. Planta Medica 1991;57:119-21.
12. Igaku A, et al. The effect of glycyrrhizin and glycyrrhetic acid on production of superoxide and hydrogen peroxide by macrophages. Chem Abstracts 1983;98:155082a.
13. Chavali SR, et al. An in vitro study of immunomodulatory effects of some saponins. Intl J Immunopharmacol 1987;9:675.
14. Nara IZ. The role of interferon-gamma (IFN-gamma) producing cells in clinical immunology. Chem Abstracts 1984;35:424.
15. Sugawa I. OK432, glycyrrhizin and CCA (lobenzarit disodium) are good in vitro inducers of IFN-gamma production. Chem Abstracts 1991;114:135740j.
16. Shinada M, et al. Enhancement of interferon-gamma production in glycyrrhizin-treated human peripheral lymphocytes in response to concanavalin A and to surface antigen of hepatitis B virus. Proc Soc Exp Bio Med 1986;181:205.
17. Tubaro A, et al. Anti-inflammatory activity of a polysaccharide fraction of Echinacea angustifolia. J Pharm Pharmacol 1987;39:567.
18. Tragni E, et al. Anti-inflammatory activity of Echinacea angustifolia fractions separated on the basis of molecular weight. Pharmacol Res Comm 1988;20(V Suppl);87.
19. Müller-Jakic B, et al. In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from Echinacea and Achillea species. Planta Medica 1994;60:37.
20. Stimpel M, et al. Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant echinacea. Infect Immun 1984 Dec;46(3):845.
21. Luettig B, et al. Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea. J Natl Cancer Inst 1989 May;81(9):669.
22. See DM, et al. In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology 1997;35:229.
23. Burger R, et al. Echinacea-induced cytokine production by human macrophages. Intl J Immunopharmacol 1998;19(7):371.
24. Steinmüller C, et al. Polysaccharides isolated from plant cell cultures of Echinacea purpurea enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes. Intl J Immunopharmacol 1993;15(5):605.
25. Roesler J, et al. Application of purified polysaccharides from cell cultures of the plant Echinacea purpurea to mice mediates protection against systemic infections with Listeria monocytogenes and Candida albicans. Intl J Immunopharmacol 1990;15(5):605.
26. Voaden DJ, et al. Tumor inhibitors. Identification and synthesis of an oncolytic hydrocarbon from American coneflower roots. J Med Chem 1972;72(6):619.
27. Coeugniet EG, et al. Immunomodulation with Viscum album and Echinacea purpurea extracts. Onkologie 1987 Jun; 27.
28. Sun Y, et al. Preliminary observations on the effects of the Chinese medicinal herbs Astragalus membranaceus and Ligustrum lucidum on lymphocyte blastogenic response. J Biol Response Modifiers 1983;2(3):227.
29. Yeung H. Handbook of Chinese herbs and formulas. Volume 1. Los Angeles: Institute of Chinese Medicine; 1985. p 405.
30. Sun Y, et al. Immune restoration and/or augmentation of local graft versus host reaction by traditional Chinese medical herbs. Cancer 1983;52:70.
31. Lau B, et al. Chinese medicinal herbs inhibit growth of murine renal cell carcinoma. Cancer Biotherapy 1994;9(2):153.
32. Yoshida Y, et al. Immunomodulating activity of Chinese medicinal herbs. Intl J Immunopharmacol 1997:19(7):359.
33. Liang H, et al. The effect of astragalus polysaccharides on cell mediated immunity (CMI) in burned mice. Chin J Plast Surg Burns 1994 Mar;10(2):138.
34. Rittenhouse JR, et al. Chinese medicinal herbs reverse macrophage suppression induced by urological tumors. J Urol 1991 Aug;146(2):486
Return to the IMMUNITY AND NUTRITION Page