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Andosan?-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from Agaricus blazei Mushroom

Authors:
Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom
Geir Hetland1,3*, Stig Palm Therkelsen2, Ivo Nentvich1 and Egil Johnson2,3
1Department of Immunology, Oslo University Hospital, Oslo, Norway
2Department of Gastro-enterological Surgery, Oslo University Hospital, Oslo, Norway
3Institute of Clinical Medicine, University of Oslo, Oslo, Norway
*Corresponding author: Prof. Geir Hetland, Department of Immunology, Oslo University Hospital -Ulleval, Kirkev 166, 0407 Oslo, Norway, Tel: +47 2211 8878; Fax:
+47 2211 8500; E-mail: geir.hetland@medisin.uio.no
Received date: December 15, 2015, Accepted date: April 17, 2015, Published date: April 24, 2015
Copyright: © 2015 Hetland G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Andosan™ is an extract prepared from medicinal Basidiomycetes mushrooms, mainly Agaricus blazei Murill
(AbM) (82%), but it also contains Hericeum erinaceus (He) (15%) and Grifola frondosa (Gf) (3%), all of which have
immunomodulating properties. Whereas He and Gf have been used in traditional Chinese and Japanese medicine
against cancer, AbM originates from Brazilian rain forest and was used locally and later abroad as health food for
the prevention of a range of diseases, including chronic hepatitis, diabetes and cancer. The mushrooms’ health
effects are probably due to their content of β-glucans and other smaller immunomodulating polysaccharides and
proteoglucans. These effects are mediated through their stimulation of innate immune cells, such as monocytes, NK
cells and dendritic cells, and the amelioration of a skewded Th1/Th2 balance and of inflammation. Here, we give an
overview of the anti-allergic effects of Andosan™ in a mouse model for allergy and anti-inflammatory effects both in
vitro, in healthy individuals and in patients with inflammatory bowel diseases.
Keywords: Andosan™;
Agaricus blazei
; Allergy; Inflammation; IBD
Introduction
Atopy is a condition where the immune system reacts to common
substances in the environment (allergens) with a genetically
determined overproduction of allergen specific antibodies of IgE
isotype. This reaction is known as the type-I hypersensitivity reaction
according to Coombs and Gell. The atopic phenotype can simply be
characterized as the dominance of the Th-2 type over the Th 1 type
immune response. Allergic inflammation is the important part of the
type-I allergic reaction. Why atopic individuals react to common
allergens with the Th-2 mediated mechanism is not entirely known.
Influence of colonisation with different intestinal microbiota during
early infancy, impact of early infant nutrition, exposure to allergens
and other little-known factors of prenatal and postnatal period are
hypothesized.
The clinical units of so called atopic disease are allergic rhinitis
(rhinoconjunctivitis), allergic bronchial asthma and atopic eczema.
Allergies to insect venoms and drugs are not considered to be due to
the atopic phenotype and heredity does not seem to play an important
role in the disease manifestation.
Atopic diseases affect approximately 20-25% of the population in
the developed countries resulting in diagnosis and treatment of atopy
being a major health political problem. For these reasons, scientists are
looking for methods of early diagnosis and effective prevention of
atopic disease. Although some prophylactic measures have been
documented to have some limited effects (e.g. restriction of passive
smoking, prolonged breastfeeding) on the development of atopic
disease, until now, there are no measures known that provide a cheap,
efficient, simply accessible and long lasting protection against
development of atopy.
Immunomodulation in atopic disease
The aim in the prophylaxis and treatment of atopy is to reverse the
Th-2 dominated atopic phenotype back to the non-atopic Th-1
phenotype and thus to eliminate or alleviate clinical symptoms of the
underlying atopic disease. Immunomodulation may be largely specific,
where known allergens are administred to patients in order to achieve
specific tolerance. This is the case in the allergen-specific
immunotherapy (ASIT). Because during the allergen-specific
immunotherapy allergen extracts from natural sources (e.g. pollen
extracts) are used, it can be speculated that the overall effect of ASIT
can be attributed to a combination of allergen-specific tolerance
induction and a nonspecific immunomodulation by not exactly
characterized additional carbohydrate substances. Another form of
immunomodulation used in the treatment of atopic disease is the
biological therapy, where monoclonal antibodies directed against IgE
molecules are used, the so called anti-IgE therapy. This treatment is
currently the only approved and used non-allergen-specific
immunomodulatory treatment of atopy.
Other ways of non-specific immunomodulation of atopic disease
are so far experimental. These include downregulation of the whole
immune system targeting the adhesion molecules, therapies targeted
towards Th-2 specific cytokines, cytokine receptors or chemokine
receptors, and interfering with signaling pathway molecules [1]. These
treatments show promising results but they are certainly expensive
and possibly limited to a small group of patients. Thus,
immunomodulation by food or food supplements still remains a very
exciting form of possible atopy treatment. Immunomodulation by
food has the advantages of simplicity, low side effects and greater
Hetland et al., J Clin Cell Immunol 2015, 6:2
http://dx.doi.org/10.4172/2155-9899.1000320
Review Article Open Access
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
Journal of Clinical & Cellular
Immunology
accessibility for low-income population groups. Results of in vitro
experiments have demonstrated immunomodulatory effects of fungal
β-glucans [2,3] and are described in details below. Moreover, positive
effects of immunomodulation by food have already been described in
humans [4]. Specifically, Talbott [5] and Yamada [6] documented
positive effects of supplementation of β-glucans on symptoms of
pollen allergy. Results of the above studies demonstrate the anti-
allergic and anti-inflammatory properties of fungal
immunomodulators and give hope for the future that they could be
increasingly used in the treatment and prevention of atopy in larger
populations.
Inflammation
Inflammation is a physiological state related to antimicrobial
defence and tissue repair. However, inflammation becomes a disease
when it is chronic and unrelated to the above, as it is in immune-
related diseases such as inflammatory bowel disease (IBD) and
rheumatoid arthritis. IBD, ulcerative colitis (UC) and Crohn’s disease
(CD) is evenly distributed between the sexes and mostly affect age
groups 15-35 years. UC is an inflammation solely of the colonic
mucosa whilst CD may be transmural involving all layers of the
intestinal wall of the large and small bowel, but, more seldomly, the
gastrointestinal tract from duodenum to the oral cavity. In UC there
may be a continuous inflammation and microscopically the entire
colon is often affected, whilst in CD healthy and diseased patches of
bowel are often interspersed. The diseases are characterised by chronic
and relapsing inflammation that may cause anorexia, weight loss,
diarrhea, pain and fever. Moreover, in CD malabsorption and subileus
occur from small bowel stenosis and the transmural inflammation can
cause fistulisation to other epithelial lined organs. Common to both
diseases are extraintestinal manifestations; iridocyclitis, spondylitis
and inflamed joints with a preponderance in CD. The development of
IBD is thougth to originate from a combination of genetic and
environmental factors. Thanks to genetic studies, IBD is now
perceived as diseases with immune reactions against bowel bacteria in
genetically predisposed individuals [7]. Key insights from gene
discovery include the role of IL-23/Th-17 signalling in IBD and
defective processing of intracellular bacteria in CD, resulting in
compensatory increased Th1 cell activity [8], and defective barrier
function in UC [9], which has been associated with increased Th2
responses in that disease. For both diseases an unselective increase in
the colonic mucosa of chemokines (MIP-1ß, MCP-1, IL-8) [10] and
cytokines IL-1ß [11], IL-6 and TNFα [12] have been demonstrated. In
serum, however, fewer cytokines are studied, but increased levels of
IL-6 and TNFα were detected in both diseases, whilst increased
MIP-1ß was found in UC [13]. Gastroenterologists have been
searching for improved treatment opportunities for IBD patients who
in severe cases end up with colectomy (UC patients) or very costly
anti-TNF (Remicade or Humira) treatment (mostly CD patients),
which often must be discontinued due to serious side effects mainly
from opportunistic infections (e.g.
Pneumocystis carinii
pnemonia,
tuberculosis) in 29-38 % but also from congestive heart failure in
0.4-0.8 % of the patients, respectively [14,15] as well as resistance to
treatment. Other side effects are increased risk for melanoma (OR 1.8)
[15] like demyelination, aplastic anemia, intestinal perforation,
systemic lupus and lymphoma affected the patients in the range of
0.02–0.8 % [14].
Figure 1:
Agaricus blazei
Murill cultivated commercially for the health food market in Japan (A) and in a nursery in Brazil (B).
Edible mushrooms, foremost of the
Basidomycetes
family have had
a long and successful medicinal use especially in traditional Chinese
and Japanese medicin. Today, approximately two million people in
Japan consume
Basidiomycetes
mushrooms such as
Agaricus blazei
and
Ganoderma lucidum
as an immune response modifier for
prevention of cancer or as nutritional support during chemotherapy
and for chronic inflammatory conditions such as hepatitis (commun.
Dr. V Badmaev, Badmaev Natural Drug Foundation, NY). Medicinal
herbs have been used in traditional medicine based on empiric
observations and their use has scientific merit because many active
substances with specific medical applications have been identified in
such herbs, e.g. acetyl salicylic acid, atropin, digitoxin and morphine.
Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 2 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
Examples of substances derived from fungi are the antibiotics,
penicillin and griseofulvin, and the immunosuppressant, cyclosporine
A, that has enabled organ transplantation. In mushrooms the
macrofungi substances with a range of therapeutic effects have been
detected [16], including chemically highly diversified anti-
inflammatory compounds, which include polysaccharides, terpenoids,
phenolic compounds, and other lowmolecularweight molecules [17].
Agaricus blazei
Murill (AbM), first described in 1893 as
Agaricus
subrufescens
and also known as
Agaricus rufotegulis
[18] is related to
the champignon (
Agaricus bisporus
). It was rediscovered in 1970
growing naturally in a coastal rain forest area near Piedade in
Southern Brazil where it was used as food and also against cancer and
various diseases [16]-hence it became also known as
Agaricus
brasiliensis
[19]. Later, this mushroom was taken to Japan for
cultivation as health food (Figure 1A) [18], but it is now also cultivated
locally in Brazil for commercial purposes (Figure 1B). The particular
mushroom extract brand Andosan™ discussed here, is a well-defined
mixture of extracts from the
Basidiomycetes
mushrooms AbM (sub-
species Heineman) (82.4%),
Hericium erinaceus
(synonym:
Hericium
erinaceum
) (He) (14.7%), and
Grifola frondosa
(Gf) (2.9%), grown in
Gifu-ken, Japan, and developed by ACE Co. Ltd., Japan, in
collaboration with researchers at the nearby Shinshu University,
Faculty of Agriculture, in Nagano-ken, Japan.
There are many studies on the immuno-modulating properties of
Agaricus blazei
Murill (AbM) and also pre-clinical and a few clinical
reports on effects of AbM against cancer, chronic hepatitis and
diabetes [20,21]. Both He and Gf have been used in Chinese medicine
against cancer, which is also found in mouse models [22,23] in
addition to immunomodulatory properties [24,25]. Thus, some of the
traditional medicinal uses of these mushrooms have been
documented. The anti-allergic and anti-inflammatory research with
Basidiomycetes
and Andosan™ are discussed in this review, which is
based on 1st authors presentation at the Immuno Summit 2014
meeting in Baltimore.
Mechanism of Action-Immunomodulation
The fruiting body of AbM is rich in immunomodulating β-glucans
[26], which is main part of the cell wall cytoskeleton in yeast, fungi and
mushrooms. Such β-glucans have been found to have anti-cancer and
anti-infection effects when given i.p. in mouse models [26-29]. AbM
has adjuvant effects in hepatitis B virus and foot-and-mouth disease
DNA vaccines in mice owing to humoral and cellular responses
[30,31].
AbM is shown to have antitumor effects against fibrosarcoma,
myeloma, and ovarian-, lung-, colon- and prostate cancer in mouse
models [32-36]. In patients with gynecological cancer, placebo-
controlled AbM add-on treatment to chemotherapy was reported to
increase NK cell activity in blood and improve the patients quality of
life [37]. At Oslo University Hospital (OUH) Dr. Tangen and colleges
have studied patients with multiple myeloma undergoing high-dose
chemotherapy, given add-on placebo-controlled treatment with the
AbM-based Andosan and found immunomodulatory effects: There
was reduced IL-1β receptor antagonist levels in plasma indicating anti-
inflammatory effect, and increased T regulatory cells and plasmacytoid
dendritic cells (DC) in blood as well as increased expression of genes
for killer immunoglobulin receptor and MHC antigens, which are
important for antigen presentation [38]. Although such a trend was
noted, too few patients were included in that study to show
significantly improved survival or increased time to new treatment.
The effects above are brought about by AbM stimulation of
monocytes, granulocytes and NK cells via TLR2 [39], and probably
dectin-1 and CD11b/18 [40-42], giving increased cytokine production
[43,44], upregulation of adhesion molecules on leukocytes [45], and
dendritic cell activation [46,47]. In vitro stimulation of monocytic cells
by Andosan AbM extract has shown increased expression of genes
related to immune function [48]. Of special interest for our study of
inflammatory bowel inflammation is upregulation of the gene for
IL-23. In vivo, oral intake of Andosan for 7 days by a few patients with
chronic HCV infection gave an insignificant reduction of HCV load in
blood but increased the expression in peripheral mononuclear
leukocytes of genes related to G-protein-R-signalling, cell cycling and
transcriptional regulation [49]. While G protein–coupled-receptors
are for chemotaxins such as IL-8 chemokine, leukotriene 4B, the
complement activation product C5a and bacteria-derived formyl
peptides and are associated with inflammation and microbial defence,
the regulation of cell cycling and transcription is rather linked to
tumor defence.
The reason for the observed forceful and swift engagement of innate
immunity and subsequently scewing of adaptive immunity away from
Th2 and towards Th1 responses when encountering contact with an
edible and harmless mushroom such as AbM, is its shearing of
pathogen-associated molecular patterns (PAMP) with other highly
poisonous and health-threatening fungi and the bigger fungi;
mushrooms. Such fungi and mushrooms are usually a health threat
because of the action of their toxins; e.g. muscimol from
Amanita
muscaria
and the vasoconstrictor ergotamine from
Calviceps
purpurea
, or invasion in immune-deficient patients (e.g.
Aspergillus
fumigatus
) or normal individuals (e.g.
Stachybotrys chartarum
).
PAMP, such as β-glucans form the main cell wall skeleton in
mushrooms and fungi are recognized immediately by so-called
pattern-recognition receptors (PRR), such as TLR2, dectin-1 and CR3
[41,42,50]. However, the anti-allergic effects of Andosan, descibed
below, are most probably not due to β-glucans because we have
previously found that β-glucans from yeast rather increased the
allergic response to ovalbumin in mice [51]. As suggested below,
smaller molecules may be responsible for these effects. The anti-
allergic effect of AbM confirmed by others in OVA-sensitized mice,
was concluded as being due to activation of macrophages by epithelial
cells and a subsequent differentiation of naïve T cells into Th1 cells
[52]. The proposed anti-inflammatory effect of Andosan agrees with
the antitumor properties of AbM because inflammation is a driving
force in cancer, which has a tendency to develop following local
chronic inflammation, e.g. colon cancer after ulcerous colitis,
hepatocellular carcinoma after chronic hepatitis, pancreas cancer after
chronic pancreatitis etc.
Pharmacokinetics and Potential Drug-Herb
Interactions
There is a general problem regarding up-concentration in
mushrooms of heavy metals, which becomes evident if they are
cultivated on poluted soil, and also of radioactivity, which became
well-known after the Tchernobyl catastroph when there was
restriction on consumption of meat from reindeer and sheep grazing
in areas with radioactive fall-out. There are conflicting opinions
concerning the safety of agaritine, a hydralazine-containing
compound, that is found in AbM. Whereas one report says it may be
Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 3 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
toxic and cancerogenetic in animals [53], another documents agaritine
as an anti-tumor substance against leukemic cells [54]. Moreover, a
toxicity study over two years in rats rather found that animals
ingesting the highest AbM concentration lived the longest, presumably
due to reduced cancer development [55].
Herb-drug interactions are associated with cytochrome P-450
metabolism and the trans-membrane efflux pump P-glycoprotein (P-
gp) that is present in normal intestinal lumen where it may limit drug
absorption, as well as in the liver, where it may increase excretion of
the drug [56]. Among other herbal remedies, a fermented extract of
the
Agaricus blazei
Murill (Gold Label) from Japan that was later trade
marked as Andosan™, was investigated at the Department of Cancer
Research and Molecular Medicine, Norwegian University of Science
and Technology, Trondheim, Norway, for in vitro inhibitory potential
on P-gp-mediated transport of digoxin in the Caco-2 intestinal cell
line. It was found that AbM (3.8 mg/ml) inhibited P-gp (i.e., net
digoxin flux (IC50)) in vitro in a similar concentration as did green tea,
without affecting viability of the cells [56]. Hence, AbM may interact
with P-gp substrates such as: vinblastine and vincristine anticancer
agent, digoxin cardiac agent, cyclosporine immunosuppressive agent
[57] and loperamide anti-diarrhea agent-hence, it should not be given
to individuals using such drugs. AbM should also not be given
together with other P-gp inhibitors such as verapamil and quinidine.
When the same researchers tested this particular AbM extract for in
vitro inhibition potential on cytochrome P-450 (CYP3A4 isoform)
metabolism, it was found to inhibit it (IC50: 1.3 mg/ml) but 20 times
less than did green tea [58]. The P-450 enzyme is involved in the
metabolism of 50% of drugs [59] and is therefore also of interest for
drug-herb interactions, especially with regard to cytotoxic
chemotherapeutics that have narrow therapeutic windows [60].
Researchers Engdal and Nilsen [58] concluded that, “although
Agaricus
(read: Andosan™-then known as Agaricus Gold Label from
ACE Co, Japan) inhibited CYP3A4 (read: cytochrome P-450
metabolism) in vitro, clinical relevant systemic or intestinal
interactions with CYP3A4 were considered unlikely. Moreover,
Andosan has also been tested at an Olympic committee-approved anti-
doping facility in Oxford (HLF Sport Science), and found by liquid
chromatography to be free of any of the 130 illegal substances on the
international anti-doping drug list, and further by gas chromatography
to be free of steroids and thus cleared for use against injury- and
exercise-related inflammation by competing athletes. Hence, Andosan
does not contain any of the above substances on the anti-doping list,
some of which may interfere with other drugs.
Allergy
Mould and fungi are risk factors for allergy and asthma in damp
indoor environments or when used as insecticid [61,62] and have been
shown to adjuvate allergy development in a mouse model [51]. When
working at The Norwegian Institute of Public Health, Oslo, and
searching for new principles for combating allergy/asthma and multi-
resistant infections, G Hetland set out to examine possible anti-allergic
properties of immunomodulating substances used for chronic
infections in traditional medicine and health food. The approach was
based upon the Th1/Th2 dichotomy hypothesis [63], saying that a
putative immunomodulating substance with anti-microbial effect
would do so by inducing or enhancing a Th1 response that would
result in a reciprocal reduced Th2 response in the individual. Since
there has been much focus in Japan on medicinal benefits of AbM, it
was of interest to examine this mushroom in the allergy model.
However, since the mouse allergy model is more cumbersome then the
rapid and robust pneumococcal sepsis model in mice [29], the latter
was employed to screen for biological activity of new substances.
Hence, we compared in a blinded fashion the efficacy of 5 different
AbM extracts from main Japanese producers of health food in the
bacterial sepsis model in mice, using S.
pneumoniae
6B i.p. for
challenge. In this comparison, only extract A gave a significant
reduction in bacteremia and increase in survival vs saline (PBS)
control (p<0.05) [40] (Figure 2), so this extract was chosen for further
work in the allergy model and then for human studies later on after it
had been labeled Andosan™.
Figure 2: Bacteremia (A) and survival (B) of mice challenged with
Streptococcus pneumoniae
2h after oral administration of different
AbM extracts [40].
As described by the scheme for the experiments in the murine
allergy model, Andosan™ or PBS was given p.o. 1 day before or 3 weeks
after immunization s.c. with the model allergen, ovalbumin. After 26
days the mice were sacrificed, bled for serum, their spleens removed,
and the spleen cells cultivated 1 day further with Andosan or
phosphate-buffered saline (PBS) (Table 1) [64]. ELISA analyses were
used for specific anti-ovalbumin IgE (Th2 response) or control IgG2a
(Th1 response) antibodies in serum, and IL-4 and IL-5 Th2 type
cytokines, and IL-2 and IFNγ Th1 type cytokines in spleen cell culture
supernatants.
We found that Andosan™ AbM-based extract protected against
allergy in mice because there was less IgE antibodies (Th2 response)
against the ovalbumin allergen in mice given Andosan™ before
ovalbumin immunization (Figure 3) [64]. There was also a tendency to
more control IgG2a antibodies (Th1 response in the mouse) against
ovalbumin in mice given Andosan™ before the ovalbumin
immunization. Moreover, since there were significantly less IgE
antibodies against ovalbumin in mice given Andosan™ after ovalbumin
immunization, the mushroom extract also had a therapeutic effect on
Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 4 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
OVA allergy. The effect of Andosan in cultures of spleen cells from the
animals above was the following: We observed significantly less Th2
cytokines (IL-4 and IL-5) relative to Th1 cytokines (IL-2 and IFNγ) in
spleen cell cultures from ovalbumin-sensitized mice that were given
Andosan™ AbM-based extract either before or after the ovalbumin
immunization [64].
Exp#
#Mice per group,
strain
Treatment D-1
(pre-OVA) (200 µl gavage)
Immunization D 0 OVA (10
µg)+ Al(OH)3 s.c.
Treatment D 19
(post-OVA) (200 µl
gavage)
Boosting D 20 OVA
(10 µg) s.c.
Sacrifice D 26
Harvest
116 NIH/OlaHsd AndoSan/PBS p.o. Taibase - Taibase Serum, spleen
216 NIH/OlaHsd - Taibase AndoSan/PBS p.o. Taibase Serum, spleen
308 NIH/OlaHsd
AndoSan/PBS/dialysed
Andosan p.o. Taibase AndoSan/PBS p.o. Taibase Serum
Table 1: Experimental design for murine allergy model
Figure 3: Levels of IgE anti-ovalbumin antibodies in serum of mice
given Andosan™ or saline (PBS) by gavage 1 day before
immunization with ovalbumin s.c. [64].
When prior to OVA sensitization the mice were given Andosan™
that had been dialysed against a membrane with cut-off 12.5 kD, the
observed reduction in specific IgE anti-OVA antibodies in serum was
rendered not statistically significant (Figure 4). Hence, small molecular
substance(s) in Andosan contribute(s) to its anti-allergy effect. Such
substances are not β-glucans, both because they are usually bigger
molecules and because we have previously shown that a β-glucan from
yeast rather had a positive adjuvant effect on OVA sensitization in the
very same allergy model in mice [51]. Moreover, Andosan has been
shown to contain far less β-glucans than anticipated [65], which
probably is due to the fact that it is an extract of the mycelium of the
three
Basidiomycetes
mushrooms and not of their fruiting bodies,
which for AbM is reported to be rich in β-glucans [26]. Therefore,
most probably also the anti-inflammatory effect of Andosan must be
caused by other immunomodulatory substances than β-glucans.
Together with researchers at Norwegian University for Life Sciences at
Aas, we are currently characterizing protein fractions in the Andosan
extract and examining their biological properties.
Our findings agree with the AbM-mediated amelioration of skewed
Th1/Th2 balance also observed in asthma-induced and fibrosarcoma-
bearing mice by oral administration of
Agaricus blazei
extracts [66].
There has been no clinical trial so far using Andosan as a supplement
in the treatment of atopic disease, but the outcome of such an
investigation would have been very interesting.
Figure 4: Loss of anti-allergic effect in dialysed Andosan when
given to mice by gavage in the ovalbumin allergy model.
Inflammation
When examining the safety of Andosan intake in healthy
volunteers, E Johnson and colleges detected that in contrast with the
pro-inflammatory findings in vitro [67], this mixed mushroom extract
did in fact have anti-inflammatory properties in vivo. After 12 days
oral treatment with Andosan there was a significant decrease in serum
levels of the pro-inflammatory cytokines IL-1β, TNFα and IL-6, in
addition to IL-2 and IL-17 (Figure 5). Also, there were no pathological
findings in blood tests for liver-, pancreas- or kidney function and no
detectable clinical side effects.
Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 5 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
Figure 5: Phase I study in healthy individuals given 60 ml/day of
Andosan™ orally for 12 days and cytokines measured in blood
samples [67].
Based on the anti-inflammatory findings in healthy volunteers,
patients with IBD; Ulcerous colitis and Crohn’s disease, were then
treated with Andosan in a pilot study at Oslo University Hospital,
Departments of Gastroenterologial Surgery and Medicine [68]. After
12 days of Andosan ingestion there was a significant decline in LPS-
stimulated blood samples ex vivo of pro-inflammatory cytokines
MIP-1β, MCP-1, IL-8, IL-6 and IL-1β and growth factors (Figure 6
and 7). Interestingly, in CD also IL-17, which part-takes in the
pathogenesis of the disease, and the Th-1 cytokine, IL-2, were reduced
(Figure 7). The decreased level of IL-17 disagrees with our finding of
increased expression of the IL-23 gene in Andosan stimulated
monocytic cells [48]. However, that was in vitro experiments which
cannot be readily used for in vivo application. Moreover for UC we
found less fecal calprotectin after consumption of the mushroom
extract. Some patients, although not systematically studied, even noted
reduction of symptoms including less diarrea and joint pain.
Altogether, these results pointed towards an anti-inflammatory effect
of Andosan in the IBD patients, without detection of any potential side
effects.
In a placebo-controlled, single blinded trial in 100 IBD patients (50
UC and 50 CD), at OUH, Ulleval 2014 (Therkelsen et al., manuscript
in preparation) 25 patients in each group used Andosan or placebo for
3 weeks. The patients were examined prior to, during and after intake
of Andosan or placebo with regard to disease symptom score and
quality of life as well as with blood samples for cytokines (not analysed
yet) and more. Preliminary analysis of the results indicate
improvements of clinical symptoms and fatigue after Andosan™
consumption.
Figure 6: Scatter plots with median and individual levels (pg/ml) of different cytokines in unstimulated (open circles) or LPS stimulated (1
ng/ml) whole blood (closed circles) ex vivo from 10 patients patients with UC prior to (day 0) and after Andosan™ consumption for 12 days
[68].
Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 6 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
Legumain (asparaginyl endopeptidase) is a proteolytic enzyme that
is prominently expressed in mammalian tissues and solid tumors [69].
We have recently found that Andosan and isolated carbohydrate
fractions thereof inhibit the activity of the tumor-associated and pro-
inflammatory protease, legumain in macrophages [65].
Another indication of the anti-inflammatory effect of Andosan, is
its effect in top athletes who experience inflammation after hard
training and injuries. Swimmers and Nordic skiers also tend to
develop exercise-related asthma. Moreover, since AbM extract
improved quality-of-life in a clinical study with cancer patients on
chemotherapy [37] and chemotherapy similar to streneous exercise
breaks down tissues before regeneration, elite swimmer Alex Hetland
suggested that an AbM extract such as Andosan may also help
improve restitution during tough training periods. He tested this out
in a survey with his team of professional swimmers at Club Wolverine,
Ann Arbor, MI, USA in the 2011/2012 winter training before London
Olympics and the World Swim Championship in Istanbul, Turkey, the
same year. The results after 3 months’ intake of Andosan™, which had
been cleared by an approved UK anti-doping laboratorium, was
improved recovery after training, less illness and improved
performance [70].
Figure 7: Scatter plots with median and individual levels (pg/ml) of different cytokines in unstimulated (open circles) or LPS stimulated (1
ng/ml) whole blood (closed circles) ex vivo from 11 patients patients with CD prior to (day 0) and after Andosan™ consumption for 12 days
[68].
Conclusions
Our report agrees with AbM-induced anti-inflammatory and anti-
allergic effects found in mouse bone marrow-derived mast cells [71],
the inhibitory effect on mast cell-mediated anaphylaxis-like reactions
in mice [72], and the amelioration of skewed Th1/Th2 balance in
asthmatic [66] and allergic mice [52]. On the other hand, it disagrees
with reports on proatherogenic and proinflammatory effects of AbM
in a mouse model for atherosclerosis [73] and a clinical randomized
trial that found no immunomodulatory effect in elderly women who
received dried AbM extract [74]. However, most of the literature
supports the anti-inflammatory and anti-allergic findings done with
the AbM-based Andosan ingredient. In line with this and the
autoimmune aspect of diabetes [75] is also the observations that AbM
ameliorates diabetic disorders in murine models [76,77], as well as in a
clinical study on insulin resistance type 2 diabetes [21].
The overall role of Andosan in immuno-modulation and disease
control seems to be the stimulation via specific receptors of antigen-
presenting cells such as monocytes and dendritic cells, giving an
increased Th1 and reciprocal decreased Th2 response resulting in
enhanced attack on microbes and tumor cells and lower allergic and
asthmatic reactions. The tumor attack is enhanced by the activation of
NK cells and the antigen-presentation by the upregulation of MHC
antigens on leukocytes. The anti-inflammatory effect of Andosan is
evidenced by the anti-allergic effect in a mouse model, the reduction in
proinflammatory cytokines in serum of both healthy individuals and
IBD patients. In addition, the mushroom extract reduced activity of
the tumor-associated and proinflammatory protease legumain, in
vitro, and seemed to improve restitution in athletes and be beneficial
for exercise-related asthma. In the IBD patients, the decline in pro-
inflammatory cytokines detected in plasma must be partly responsible
for the improvements observed in their clinical symptoms. How
Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 7 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
Andosan actually influences Th1/Th2 responses and IL-23/Th17
signalling in IBD patients, will be revealed in the newly finished
placebo-controlled clinical study in 100 UC and CD patients by
Therkelsen and collaborators.
Disclosure
G Hetland is co-founder of Immunopharma AS, Norway, which
aims at developing Andosan into adjuvant hospital treatment for
patients with severe and non-curable diseases. The other authors have
no interest to declare.
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Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
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Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
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Citation: Hetland G, Therkelsen SP, Nentvich I, Johnson e (2015) Andosan™-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from
Agaricus blazei Mushroom. J Clin Cell Immunol 6: 320. doi:10.4172/2155-9899.1000320
Page 10 of 10
J Clin Cell Immunol
ISSN:2155-9899 JCCI, an open access journal Volume 6 • Issue 2 • 1000320
... AbM is found to induce apoptosis or programmed cell death in ovarian cancer cells of humans 16 . In mouse models of fibrosarcoma, myeloma, prostate cancer, ovarian as well as lung cancer AbM showed antitumor activities, also in human studies against gynecological cancer (marked Natural Killer cell activity and quality of life) and leukemia 19 . ...
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