Immunomodulation: Enhancing Immune Function With Herbal Supplements - The Right Way

Article by Don Goldberg

“Immunomodulation describes the ability of an herb, nutrient, or other substance to promote healthy immune function. Our immune systems are a complex interplay of cells that dictate the body’s resistance to infections. These include macrophages, lymphocytes (B and T), and other factors known as cytokines (e.g., interleukin, interferon, qnd tumor necrosis factor). Lymphocytes, the body’s primry defense against viral infections, have been a primary area of focus with regard to HIV infection.
“A common denominator among immunomodulating herbs is the presence of complex sugar molecules known as polysaccharides. Polysaccharides improve the activity of lymphocytes and other cells of the immune system, thus strengthening the overall immune response.
“Perhaps the most well-known example of an immunomodulating herb is echinacea. . .echinacea simply increases all aspects of the immune response. . . the perfect short-term boost that many immune systems require from time to time.
“However, a ‘get busy’ immune stimulant like echinacea is not for everybody. If your immune system is already overactive, as is the case with autoimmune diseases, you should avoid echinacea. It’s also not recommended for progressive diseases such as multiple sclerosis. Finally, the jury is still out on whether echinacea should be used by persons with HIV infections.”
This is why many experts in the field believe that these conditions are the domain of the adaptogenic herbs. Adaptogens such as astragalus, ashwagandha and eleuthero “tend to enhance the immune system by way of a balancing approach, as opposed to the more nonspecific approach taken by echinacea. This means adaptogens can be used to treat conditions in which the immune system is either depressed or overactive.”
Donald Brown, N.D., in his book Herbal Prescriptions for Better Health, Prima Publishing, lists the following immune-related conditions that may be treated with herbal adaptogens:
- HIV infection
- Chronic fatigue syndrome
- Chronic hepatitis
- Cancer patients recovering from radiation or chemotherapy
- Systemic lupus erythematosus
He cautions, of course, that with most of these conditions, immune-enhancing actions “represent only one aspect of a complete health care program.”
Dr. Brown then continues, with the following observation: “Some mushrooms, including shiitake, reishi, and maitake, contain a high concentration of polysaccharides. These polysaccharides, like those of immunomodulating herbs, affect the immune system. Traditionally employed as tonics, these mushrooms have many of the same applications as the herbal adaptogens.”
In fact, when it comes to serious immune enhancing and/or immuno-modulating agents, the mushroom extracts he mentioned above–reishi, maitake and shiitake–have taken front stage when it comes to clinical research and treating serious immune-related medical conditions.
Products such as the Willner Chemists Phyto-Tech Mushroom Extract Complex are now available, providing combinations of these powerful immuno-modulating agents. The Phyto-Tech Mushroom Extract Complex contains a blend of Shiitake mushroom, Reishi mushroom, Maitake mushroom and fresh Ashwagandha Root. The information that follows, summarizing the current research on each of these four extracts, was taken from current reference databases, including Memorial Sloan Kettering, NHI, and Natural Standard.
Maitake (Grifola frondosa), is also known by the following common names: King of mushrooms, dancing mushroom, cloud mushroom, hen of woods.
Maitake is a mushroom that traditionally has been used in Japan and China as part of the diet and to treat diabetes and hypertension. Current interest in Maitake is related to its ability to stimulate immune activity. Like other medicinal mushrooms, maitake contains a complex sugar called a beta-glucan. In laboratory studies, maitake extract was able to stimulate various cells and factors in the immune system. Studies in animals show that it slows the growth of certain tumors and lowers blood glucose (sugar) levels.
Maitake is currently being used to enhance immune function, prevent and treat cancer, and to help manage diabetes.
Scientific Support:
Maitake demonstrated antitumor effects (16), enhanced bone marrow colony formation, reduced doxorubicin toxicity (11), and inhibited tumor metastasis in vitro (13). In a study done in mice, oral maitake extract promoted maturation of hematopoeitic cells to functionally active myeloid cells and enhanced peripheral blood leukocyte recovery following chemotoxic bone marrow injury (17). A novel polysaccharide, MZF, was shown to induce dendritic cell maturation and enhanced antitumor response (20).
Maitake also enhanced interferon activity against bladder cancer cells (18) and alleviated inflammation associated with inflammatory bowel disease (19).
In a small non-controlled study, tumor regression or significant improvements in symptoms were observed in half of the subjects using Maitake extract (5). In another study of postmenopausal breast cancer patients, oral administration of maitake extract was shown to have immunomodulatory effects (14). More studies are underway to establish Maitake’s anticancer potential.
Maitake extracts exhibited hypoglycemic effects in a few studies (9) (12). Preliminary data suggest that maitake may be useful in inducing ovulation in patients with polycystic ovary syndrome (PCOS) (22).
Mechanism of Action:
Maitake is thought to exert its effects through its ability to activate various effector cells, such as macrophages, natural killer cells, and T cells, as well as interleukin-1 and superoxide anions (2) (3) (4) (13). Maitake extract enhanced the growth and differentiation of mouse bone marrow cells treated with doxorubicin, a chemotherapeutic agent (11). In addition, maitake extract may modulate antigen presentation as evidenced by protection of mice against tumor implantation following transfer of dendritic cells from tumor-bearing mice that were treated with maitake extract (15).
Studies also suggest possible hypoglycemic activity (9). Alpha-glucan from maitake may increase insulin sensitivity (12).
Shiitake Mushroom (Lentinula edodes) is also known by the following common names: Forest mushroom, lentinula, pasania fungus, lentinula, hua gu
The medicinal properties of Shiitake mushroom are attributed to a polysaccharide (sugar molecule) named lentinan, on which extensive research has been done. Lentinan is a polysaccharide called a 1,3 beta glucan. In laboratory tests, lentinan does not kill cancer cells directly, but enhances a number of aspects of the immune system, which may aid in the slowing of tumor growth. Lentinan also kills viruses and microbes directly in laboratory studies. Most studies involving lentinan involve intravenous or intramuscular injections. It is uncertain whether ingestion of shiitake mushrooms provides similar effects. One clinical trial has shown shiitake extract alone is not an effective treatment for prostate cancer. More studies are needed.
Scientific Support:
Shiitake mushroom, native to East Asia, is cultivated worldwide for its purported health benefits. The fresh and dried forms of the mushroom are commonly used in East Asian cooking. It is also valued as an anticancer agent.
Lentinan (1,3 beta-D-glucan), a polysaccharide isolated from Shiitake, has been well studied and is thought responsible for Shiitake's beneficial effects. It was shown to have anticancer effects in colon cancer cells (1), which may be due to its ability to suppress cytochrome P450 1A enzymes that are known to metabolize pro-carcinogens to active forms (2).
Lentin, the protein component, has strong antifungal properties, inhibits proliferation of leukemic cells, and suppresses the activity of human immunodeficiency virus-1 reverse transcriptase (3). Studies conducted with Shiitake extracts in vitro and in mice revealed the mushroom's antiproliferative (4), immunostimulatory (4), hepatoprotective (5), antimutagenic (6), and anticaries (7) properties, but a clinical trial failed to show effectiveness in the treatment of prostate cancer (8).
Results from two small studies of HIV-positive patients who were administered intravenous lentinan showed a statistically insignificant increase in CD4 cells and neutrophil activity in some patients; researchers also reported severe adverse effects in some patients (9).
But improvements in quality of life and survival were seen with an oral formulation of superfine dispersed lentinan in patients with hepatocellular carcinoma (15), gastric (16), colorectal (17), and pancreatic (18) cancers.
Mechanism of Action:
Lentinan possesses immune-regulatory, antimicrobial, anti viral, and cholesterol-lowering effects (13). The water extract of shiitake decreased IL-1 production and apoptosis in human neutrophils. However, it increased apoptosis in U937 monocytic cell line (14). Lentin, the protein component of shiitake, has strong antifungal effects. An in vitro study has shown lentin can inhibit the proliferation of leukemia cells and suppress the activity of human immunodeficiency virus-1 reverse transcriptase (3).
Reishi Mushroom (Ganoderma lucidum) is also known by the following common names: Ling zhi, ling chi, lin zi, mushroom of immortality
Reishi mushroom has antioxidant properties and may enhance immune responses.
Reishi mushroom contains complex sugars known as beta-glucans that stop the growth and prevent spreading of cancer cells. When animals were fed beta-glucans, some cells of their immune system become more active. Limited data from clinical studies suggest Reishi mushroom can strengthen the immune responses in humans.
In addition, reishi mushrooms contain sterols that can act as precursors to hormones in the body, along with substances called triterpenes that may have blood pressure-lowering and anti-allergy (anti-histamine) effects. Reishi mushrooms have also been shown to slow the process of blood clotting.
Scientific Evidence:
Derived from the cap and stem of the mushroom, reishi mushroom is used as an immune stimulant by patients with HIV and cancer. The active constituents are thought to include both beta-glucan polysaccharides and triterpenes (1). Extracts of reishi can stimulate macrophages and alter the levels of TNF and interleukins (2) (3) (4) (5). Reishi also inhibited platelet aggregation (11) (12) and improved lower urinary tract symptoms (LUTS) in men (9) (10) (20).
In vitro and animal studies indicate that reishi has chemopreventive effects (21), alleviates chemotherapy-induced nausea (13), enhances the efficacy of radiotherapy (22), and increases the sensitivity of ovarian cancer cells to cisplatin (27). It was also effective in preventing cisplatin-induced nephrotoxicity (28).
In small clinical studies, reishi increased plasma antioxidant capacity (6) (7), and enhanced immune responses in advance-stage cancer patients (8). Remission of hepatocellular carcinoma (HCC) has been reported in a few cases (23).
Mechanism of Action:
The triterpenes are reported to have adaptogenic and antihypertensive, as well as anti-allergic effects. In addition, they may inhibit tumor invasion by reducing matrix metalloproteinase expression (16) and tumor metastases by limiting attachment to endothelial cells (17). A number of polysaccharides present in reishi, such as beta glucans, have demonstrated antitumor and immunostimulating activities (18). They can induce the maturation of normal and leukemic monocytes into dendritic cells (19). The adenosine in reishi is thought responsible for the inhibition of platelet aggregation (11). Extracts of reishi have demonstrated the ability to stimulate macrophages and to alter the levels of TNF and interleukins (2) (3) (4) (5). Reishi can increase plasma antioxidant capacity (6) (7) and enhances immune response in advance-stage cancer patients (8). Furthermore, reishi extracts can inhibit 5-alpha reductase, an important enzyme that converts testosterone to dihydrotestosterone and is upregulated in benign prostatic hyperplasia (9)
Ashwagandha (Withania somnifera) is also known by the common names  Indian ginseng, Winter cherry.
Ashwagandha is a popular Ayurvedic herb. Studies show that it has anti-inflammatory effects. Ashwagandha also relaxes the central nervous system in animals. Laboratory studies found that ashwagandha kills some cancer cells and enhances some immune cells possibly by damaging the cancer cells' ability to generate the energy it needs to reproduce. Ashwagandha also reduces the level of an important antioxidant in tumor cells, which may enhance the ability of radiation therapy to kill those cells. While animal and laboratory tests have shown that Ashwagandha slows the growth of cancer cells and enhances the effect of radiation therapy, these effects have not yet been confirmed in humans.
Other purported actions of Ashwagandha include reducing fatigue, inflammation and pain, and stress.
“Ashwagandha is an adaptogen, or substance that helps protect the body against various emotional, physical, and environmental stresses. Ashwagandha is reported to have tonic or adaptogenic effects similar to the panax ginsengs.” (Www.nhiondemand.com)
Scientific Evidence:
A popular Ayurvedic herb, ashwagandha is often used in formulations prescribed for stress, strain, fatigue, pain, skin diseases, diabetes, gastrointestinal disease, rheumatoid arthritis, and epilepsy (1). It is also used as a general tonic, to increase energy and improve health and longevity (2). Externally, it can be applied as a local analgesic (3). The active constituents are thought to include alkaloids, steroidal lactones, saponins, and withanolides.
In vitro studies suggest that ashwagandha has neuroprotective (26) and anti-inflammatory properties which may protect against cartilage damage in osteoarthritis (4). Animal studies suggest antitumor, immunomodulatory, antioxidant, and anti-stress properties. In addition, improvements in hyperglycemia, hyperinsulinemia, and insulin sensitivity have been detected in an animal model of type 2 diabetes (5). Other studies indicate cytotoxic, chemopreventative, immunomodulating (8), and radiosensitizing effects (1) (9) (10) and enhancement in chromosomal stability (11).
Ashwagandha is rich in iron (2); small scale human studies suggest that it may promote growth in children and improve hemoglobin level, red blood cell count, sexual performance in adults (2), and may also be useful in treating male infertility (27). An herbal tea containing ashwagandha was shown to increase natural killer cell activity in healthy volunteers with recurrent coughs and colds (22). Data also indicate that ashwagandha may be useful in the treatment of anxiety (23). In another clinical trial, an herbomineral formula containing ashwagandha was shown to benefit osteoarthritis (13). Preliminary data suggest benefits of ashwagandha in improving balance in patients with progressive degenerative cereberral ataxias (24).
Ashwagandha also reduced growth of breast, central nervous system, colon, and lung cancer cells (6) without affecting normal cells (7). Ashwagandha may help prevent chemotherapy-induced neutropenia (12), but it has not been studied in cancer patients.
Alkaloids, steroidal lactones, saponins, and withanolides are thought to be the biologically active components of ashwagandha. Studies have pointed to cyclooxygenase (COX) inhibition as the mechanism for the herb's antiarthritic properties. In animal studies, Ashwagandha's anti-inflammatory effects were comparable to hydrocortisone (15). Microarray analysis revealed that ashwagandha represses proinflammatory gene expression, including IL-6, IL-1ß, IL-8, Hsp70, and STAT-2, and induces p38/MAPK expression in a prostate cancer cell line (16). It exhibits antioxidant effects in the brain and tranquilizing effects on the central nervous system in animals (2) possibly by influencing GABA receptor function (17). Ashwagandha may inhibit tumor growth (1) (21)and increases cytotoxic T lymphocyte production (8). In vitro studies have shown that root extracts have cytotoxic properties against lung, colon, central nervous system, and breast cancer cell lines (6). Withaferin A induces reactive oxygen species (ROS) generation and disruption of mitochondrial function in a human leukemia cell line, thereby inducing apoptosis (18). In estrogen receptor-positive (ER+) and negative (ER-) breast cancer cells, withaferin A induces apoptosis and decreased tumor size (19). Apoptosis of cancer cells by withanone is mediated through p53 (7). Withianone also has anticancer activity by binding to TPX2-Aurora A Complex (29). Other studies show ashwagandha’s cytotoxicity is related to its structure; it enhances ATPase and inhibits succinate dehydrogenase activities, impairing oxidative phosphorylation. In animal studies, ashwagandha can enhance the effects of radiation therapy (20) by reducing tumor GSH levels (10). Ashwagandha can reverse paclitaxel-induced neutropenia in mice (12). Significant toxicity was observed at high doses in animal studies (20); however, toxicity studies in humans are limited (2).
Cautions:
Do not use during pregnancy. Keep out of the reach of children. Use caution if taking anti-coagulant medication. May have a slight blood glucose lowering action.

Note: The substances discussed in this article can be found in the Willner Chemists' product, PhytoTech Mushroom Extract Complex, product code 57002

References: General
MSKCC.ORG (Memorial Sloan-Kettering Cancer Center
NHIondemand.com
Brown, Donald N.D., Herbal Prescriptions for Better Health, Prima Publishing.

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