MediMush Science Document – C October 2004

MediMush Science Documents

C. Immune modifiers from the

Shiitake mushroom

C1. SHIITAKE IMMUNE MODIFYING COMPOUNDS

C2. LENTINAN

C3. SELECTED SCIENTIFIC REVIEWS

C4. MEDICAL SUMMARY

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C1. SHIITAKE IMMUNE MODIFYING COMPOUNDS

Over the centuries many immunomodulating agents have been derived from
plants as well as mushrooms, fungi and bacteria. While many cultures have known
of the nutritional and medicinal value of mushrooms, it was the Chinese and
Japanese who embraced the positive effects that they can have on varying
conditions of health.
The shiitake mushroom (Lentinus edodes) is the second most popular edible
mushroom in the world. The Shiitake mushroom and its components has been
intensely studied for a long time with records going back over 3000 years. It is a
good sources of carbohydrates, protein and essential amino acids. It is low in fat,
have a high percentage of polyunsaturated fatty acids and also contain many
vitamins and minerals. On the medicinal side, it has been shown that the Shiitake
mushroom has anticancer, antiviral and anti-microbial properties. Also, it has been
shown to contain hypolipidemic (lowers blood cholesterol) and antithrombotic
(inhibits aggregation of blood platelets) substances. The compound credited with
these properties are primarily the polysaccharide based compounds lentinan, KS-2
and LEM all of which are extracted from the mushroom. Lentinan, a cell wall
constituent extracted from fruiting bodies or the mycelium, is a beta glucan
containing no protein, KS-2 is a predominantly α-linked peptidomannan (mannose
based polymer containing peptides) and LEM is a water soluble extract from the
mycelium of cultivated Lentinus. Of all these lentinan has been studied extensively
for immune modulating, or immune stimulating effect. Thus, it will be used here to
illustrate the function of immune stimulants from medicinal mushrooms.

C2. LENTINAN
Lentinan is a high molecular weight polysaccharide in a triple helix structure.
It does not attack cancer cells directly, but produces its antitumor effect by
activating different immune responses in the host. Lentinan is a true
immunopotentiator, as it acts as a host defence potentiator that is able to restore

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or augment the responsiveness of host cells to cytokines, hormones, and other

biological messenger substances.
This immune-potentiation occurs by stimulating the maturation,
differentiation or proliferation of cells involved in host defence mechanisms. Thus,
Lentinan has been shown to increase host resistance against various kinds of
cancer and has the potential to restore the immune function of affected
individuals.
Lentinan is in a unique class of DT-cell-oriented assistants, in which
macrophages play some part. It can activate NK-cells involved in tumour
suppression and while these cells tend not to stimulate T-killer cell activity, they
are strong T-helper cell stimulants. Lentinan inhibits synthesis of prostaglandin,
which can slow T-cell differentiation in animals and humans, as well as inhibiting
suppressor T-cell activity.
Lentinan has been shown to stimulate peripheral blood lymphocytes in vitro
to increase interleukin-2-mediated LAK-cell (lymphokine-activated killer cell) and
NK cell activity. It has also been shown to inhibit suppressor T cells activity and to
increase the ratio of activated T cells and cytotoxic T cells in the spleen when
administered to gastric cancer patients undergoing chemotherapy.
Lentinan has been shown previously to increase the capacity of peripheral
blood mononuclear cells of patients with gastric cancer, resulting in the production
of IL-1α, IL-1β and TNF-α. In its role as a host defence potentiator, Lentinan
triggers the increased production of colony stimulating factors (CSFs) and IL-3,
which correlates with the IL-1-producing activities of macrophages. Increased
production of IL-1 results in augmented maturation capable of inducing IL-2,
natural killer activating factor, and macrophage-activating factor (MAF). IL-1 also
amplifies maturation of immature effector cells to mature cells and augments
responsiveness to cytokines such as IL-2, MAF and others.

Lentinan-stimulation of dendritic cells (antigen-presenting cells that are

found in lymph nodes, spleen and thymus; follicular and interdigitating dendritic
cells, skin: Langerhans cells, and other tissues; interstitial dendritic cells) has an

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important impact on immunomodulation and anti-tumour activity. Moreover,

dendritic cell tumour-infiltration in association with killer cytotoxic T cell stimulation
and activation has been shown to have a governing role in tumour attack and
elimination.

The likely mode of immunopotentiation by lentinan involves activation of

cytotoxic macrophages, helper T cells and NK cells, and the promotion of T cell
differentiation. Thus, Lentinan restores or augments the ability of host cells to
respond to cytokines or other intrinsic bioactive factors and protect patients from
infectious disease or cancer metastases. Lentinan can also improve the
physiological constitution of host defence mechanisms by restoring homeostasis
and enhancing intrinsic resistance to disease. Homeostasis is a term given to
cellular processes, by which both negative and positive control are exerted over
the values of a variable or set of variables, and without which control the system
would fail to function.

C3. SELECTED SCIENTIFIC REVIEWS

Maeda, YY and Chihara, G (1999). Immunomodulatory Agents from
Plants. In Lentinan and other antitumoral polysaccharides, ed H Wagner,
(Birkhauser Verlag).
Antitumor activity of lentinan
Lentinan exerts prominent antitumor effects on various syngeneic and
autochthonous tumours as well as allogeneic tumours. The interesting
characteristics of the antitumor mechanisms are:
™ Lentinan does not exhibit any direct cytotoxicity against tumour cells and its
action is host mediated
™ Toxicity towards the host is not observed (LD50>100mg/kg interperitoneal
in mice)
™ Lentinan administered at high doses (80 mg/kg/day x 5) does not exhibit
any antitumor activity. This phenomenon of optimal dose suggests that

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lentinan interacts with certain substances, either cellular or humoral in the

host.
Effect on various immune and inflammatory responses
™ Lentinan has the capacity to act as T-cell immune adjuvant
™ Lentinan appears to restore and potentiate helper T-cell functions but not to
stimulate B-cells or T-suppressor cells
™ Lentinan stimulate T-cell secretions of cytokines such as IL-3, IFN-gamma,
CSF and MIF
™ Anti-tumoral activity appears to be mediated by T-helper type 1 (Th 1) cells
but not Th 2. Th 1 activation by lentinan is consistent with the fact that
lentinan stimulated delayed type hypersensitivity (DTH) against tumour
associated antigens in vivo
™ Macrophages are considered to be the first cells that lentinan comes in
contact with and activates in the host
Increase in resistance of host to infection
™ Lentinan can enhance resistance of a host to bacterial, fungal, viral or
parasitic infections. This is an advantage to cancer and AIDS patients, since
they have a deteriorated immune response which can cause serious
problems.

Suzuki, M, Takatsuki, F, Maeda, Y, Hamuro, J and Chihara, G (1994).

Lentinan: Rationale for Development and Therapeutic Potential. Clinical
Immunotherapy 2(2), 121-133.
The review looks at both animal and clinical studies on lentinan. The review
concludes that lentinan exhibits prominent antitumor, antimetastatic and anti-
infectious effects and protects against cancer recurrence and carcinogenisis. The
article suggests that at least two different mechanisms may contribute to the
antitumor effects of lentinan:
™ Augmentation of the activity of anti-tumour effector cells
™ Augmentation of infiltration of activated effector cells into the tumour

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The article reviews animal models and postulates that the therapeutic effect of
lentinan in different host-tumour systems may be variable depending on the
interaction of tumour cells and the host immune cells either surrounding or
infiltrating the tumour burden. In tumour/host systems where responsiveness to
lymphokines was suppressed, lentinan alone exerted prominent antitumor effects.

In systems where both local cellular reactions and responsiveness to lymphokines

was suppressed, lentinan alone did not exert antitumor effects and its combination
with chemotherapy and radiotherapy was required to initiate local cellular
reactions. In tumour/host systems where both lymphokine production and
responsiveness to lymphokines was suppressed, combination of lymphokines and
lentinan was required to fully express the antitumor effects of lentinan.

C4. MEDICAL SUMMARY

common names: Shiitake mushroom, Hua gu

botanical name: Lentinus edodes

chemistry/function: Shiitake is rich in proteins, fats, polysaccharides, lignans,

vitamins, minerals, and soluble fibre. Shiitake contains all eight essential amino
acids in well-balanced proportions as well as a good blend of vitamins and
minerals including vitamins A, B, B12, C, D and niacin. Lentinan (LTN), which is
the name given a highly purified polysaccharide fraction extracted from the
fruiting body of Shiitake mushrooms, is an approved drug in Japan. Some
researchers consider lentinan the most potent constituent of the Shiitake.
Commercial preparations of Shiitake typically list "Lentinus edodes mycelium"
extract (LEM), a powdered derivative of the mushroom's mycelium available
before the cap and stem mature, which provides an abundance of polysaccharides
and lignans.

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known or potential therapeutic uses: AIDS/HIV support, cancer, fatigue, hepatitis,

high cholesterol, hypertension, immune support, intestinal parasites/worms,
longevity, respiratory infections.

mechanism: Shiitake have demonstrated antifungal, anti-tumour, and antiviral

effects. The immunomodulatory action of lentinan polysaccharide is usually
considered as the most important mechanism involved in Shiitake's therapeutic
action. The antiviral effects are believed to derive from Shiitake's ability to
promote interferon production. Lentinan may also prevent the increase of
chromosomal damage induced by anti-cancer drugs.

maintenance dose: Shiitake mushrooms are commonly used as a food, especially

in China and Japan where they are highly valued as a food and as a medicinal
substance. Traditionally, one or two fresh Shiitake mushrooms are eaten daily for
preventive value. Likewise, 6 - 16 g of dried shiitake are often consumed in tea,
soup, or other dishes as part of the normal diet. However, their consumption is
not considered necessary by any governmental or institutional authorities. Optimal
levels of intake have not been established.

therapeutic dose: Most practitioners of herbal medicine prescribe extracts or

concentrated forms of Shiitake rather than whole mushrooms when seeking a
therapeutic response. LEM is usually taken at dosages of 1-3 grams, two or three
times per day, for therapeutic purposes. Shiitake is often available as a tincture,
with 2-4 ml per day being a typical dosage. Lentinan is commercially available for
clinical use but is generally administered by injection.

side effects: Individuals with allergies may experience adverse reactions to

Shiitake due to its histamine-sensitising properties. Consumption of whole Shiitake
mushrooms, especially in doses greater than 15-20 grams per day, has
occasionally been associated with mild side effects such as transient diarrhoea,
abdominal bloating, and skin rashes. LEM, which is concentrated and more easily
absorbed, is often preferred for medicinal purposes to avoid the possible digestive
upset from eating large quantities of fresh Shiitake. In a small study of healthy

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subjects Levy et al found that daily ingestion of Shiitake mushroom powder

provoked blood eosinophilia, increased eosinophil granule proteins in serum and
stool, and increased gastrointestinal symptoms in half (five of ten) of the
individuals. Lentinan has no known serious side effects.

Significant research and many case reports have documented the relatively
frequent occurrence of hypersensitivity reactions among those who cultivate and
process the mushrooms, especially with chronic indoor exposure to spores. A large
number of cases involving immunological reactions, such as rashes, and
respiratory irritation, most commonly hypersensitivity pneumonitis, have been
thoroughly documented.

toxicity: No acute toxicities have been reported or suspected as being associated

with Shiitake or LEM, even in massive doses of more than 50 mg a day for one
week. There has been one case report of an elderly Japanese woman who
suffered a fatal intestinal obstruction following ingestion of at least two whole
mushrooms and subsequent impaction.

contraindications: None known to date, except allergic sensitivity. Usage during

pregnancy has not been adequately researched to confirm safety.

nutrient affecting drug performance: Didanosine

• research: Lentinan is a polysaccharide, i.e., a complex sugar compound, derived

from Shiitake mushrooms known as a potent immune modulator. When combined
with didanosine, 2 mg of lentinan intravenously, once per week, caused significant
increases in CD4 levels up to 38 weeks, whereas ddI alone was significant at the
5% level at 14 weeks.

• nutritional support: Oral preparations of Shiitake have been used traditionally

and in modern research to enhance immune function. It is obviously uncertain as
to whether or not the findings with lentinan delivered intravenously, especially in
combination with didanosine, can be extrapolated to whole Shiitake taken orally.

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nutrient affecting drug performance: Fluorouracil

• research: Taguchi and other researchers have found that patients suffering from
advanced or recurrent, stomach and colo-rectal cancer who were administered
lentinan intravenously in combination with mitomycine C + 5-FU (MF) or tegafur
(FT) demonstrated statistically significance improvement in life span prolongation
as compare to those who were treated with MF or FT alone. These researchers
also noted that improvement of host immune responses was observed in the
group treated with lentinan, and hematological survey showed that incidence rate
of abnormal value was significantly low in LNT treated group. Similar research
suggests that lentinan may also be effective for patients with advanced or
recurrent breast cancer as an agent for supportive therapy.

nutrient affecting drug performance: Heparin and Warfarin

• reports: A watery extract of the whole shiitake has been reported to hinder
blood coagulation.

• nutritional/herbal concern: Individuals taking heparin, warfarin or other

anticoagulant medicines should refrain from consuming Shiitake beyond occasional
use in foods until they have consulted with their prescribing physician and/or a
healthcare professional trained in herbal prescribing.

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