The Effects of AHCC®, a Standardized Extract of Cultured Lentinura edodes Mycelia, on Natural Killer and T Cells in Health and Disease: Reviews on Human and Animal Studies

Abstract

Mushrooms have been used for various health conditions for many years by traditional medicines practiced in different regions of the world although the exact effects of mushroom extracts on the immune system are not fully understood. AHCC® is a standardized extract of cultured shiitake or Lentinula edodes mycelia (ECLM) which contains a mixture of nutrients including oligosaccharides, amino acids, and minerals obtained through liquid culture. AHCC® is reported to modulate the numbers and functions of immune cells including natural killer (NK) and T cells which play important roles in host defense, suggesting the possible implication of its supplementation in defending the host against infections and malignancies via modulating the immune system. Here, we review in vivo and in vitro effects of AHCC® on NK and T cells of humans and animals in health and disease, providing a platform for the better understanding of immune-mediated mechanisms and clinical implications of AHCC®.

Full text

Review Article
The Effects of AHCC®, a Standardized Extract of Cultured
Lentinura edodes Mycelia, on Natural Killer and T Cells in Health
and Disease: Reviews on Human and Animal Studies
Min Sun Shin,
1
Hong-Jai Park,
1
Takahiro Maeda,
2
Hiroshi Nishioka,
2
Hajime Fujii,
2
and Insoo Kang
1
1
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
2
Research and Development Division, Amino Up Co., Ltd., 004-0839 Sapporo, Japan
Correspondence should be addressed to Insoo Kang; insoo.kang@yale.edu
Received 7 October 2018; Accepted 20 November 2019; Published 20 December 2019
Academic Editor: Paola Nistico
Copyright © 2019 Min Sun Shin et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Mushrooms have been used for various health conditions for many years by traditional medicines practiced in different regions of
the world although the exact effects of mushroom extracts on the immune system are not fully understood. AHCC® is a
standardized extract of cultured shiitake or Lentinula edodes mycelia (ECLM) which contains a mixture of nutrients including
oligosaccharides, amino acids, and minerals obtained through liquid culture. AHCC® is reported to modulate the numbers and
functions of immune cells including natural killer (NK) and T cells which play important roles in host defense, suggesting the
possible implication of its supplementation in defending the host against infections and malignancies via modulating the
immune system. Here, we review in vivo and in vitro effects of AHCC® on NK and T cells of humans and animals in health and
disease, providing a platform for the better understanding of immune-mediated mechanisms and clinical implications of AHCC®.
1. Introduction
Mushrooms have been considered to have possible beneficial
effects in health and disease for many years by traditional
medicines practiced in different regions of the world [1].
Although the exact biological mechanisms underlying such
effects are yet to be elucidated, extracts from a group of
mushrooms are now used as dietary supplements and func-
tional foods in health conditions possibly associated with
immune dysregulations that include infections, inflamma-
tory diseases, and malignancies [1]. The effects of mush-
rooms on the immune system could stem from bioactive
polysaccharides such as beta- (β-) glucans or polysaccharide
complexes in mushrooms in that these molecules appear to
affect innate and adaptive immune responses [2, 3]. Also,
studies reported the activation of natural killer (NK) and T
cells by alpha- (α-) glucans extracted from edible mushrooms
like Tricholoma matsutake and maitake (Grifola frondosa)
[4, 5], supporting the implication of α-glucans in regulat-
ing the immune system.
AHCC® is a standardized extract of cultured shiitake or
Lentinula edodes mycelia (AHCC®) which contains a mix-
ture of nutrients including oligosaccharides, amino acids,
and minerals obtained through the liquid culture process of
shiitake mycelia [6, 7]. It is produced by Amino Up Co.,
Ltd. (Sapporo, Japan) under the trademark “AHCC®.”Here-
inafter, AHCC® and ECLM are used interchangeably in the
manuscript. The shiitake mycelia used for AHCC® are cul-
tured in a liquid medium where the mycelia proliferate and
form globular fungal bodies but not fruiting bodies [8].
AHCC® is produced through the unique manufacturing
process of culturing the mycelia followed by separation,
sterilization, and freeze-drying [8]. The most abundant
component of AHCC® is oligosaccharides which comprise
about 74% of the dry weight of AHCC® [6, 7]. Of the oli-
gosaccharides in AHCC®, about 20% are α-1,4-glucans, of
Hindawi
Journal of Immunology Research
Volume 2019, Article ID 3758576, 7 pages
https://doi.org/10.1155/2019/3758576

which a proportion is partially acylated, with a mean
molecular weight around 5000 Daltons [6, 7]. The effects of
AHCC® on immune cells of humans and animals were
reported in in vitro and in vivo studies, suggesting the possi-
ble help of its supplementation in defending the host against
infections and malignancies via modulating the immune sys-
tem [6, 9–28]. This review focuses on the reported effects of
AHCC® on natural killer (NK) and T cells given their roles
in host defense and inflammation [29–34], providing a plat-
form for the better understanding of immune-mediated
mechanisms and clinical implications of AHCC® and possi-
bly other medical mushrooms in health and disease.
2. Effects of AHCC® on Natural Killer (NK)
Cells in Infections and Malignancies
NK cells are large granular lymphocytes considered as the
first line of defense against viral infections and possibly
malignancies via secreting cytokines and expressing cyto-
toxic molecules [30, 34, 35]. Indeed, NK cells are armed with
receptors that sense signals from target cells such as infected
or tumorous cells, leading to killing [31, 34]. Impaired func-
tion or deficiency of NK cells has been associated with
increased risk of infections and malignancies in humans
and animals [34, 35]. Mushroom products have been sug-
gested to modulate NK cell activity against infected or tumor-
ous cells [36]. A recent study showed that water and ethanol
extracts of cultured mycelium from various species could
have distinct effects on NK cell-mediated cytotoxity against
tumor cells [37]. Water extracts of cultured mycelium from
medicinal mushrooms including Agaricus blazei and Gano-
derma lucidum enhanced cytotoxic activity in human NK cell
lines by upregulating the cytotoxic molecules perforin and
granulysin as well as the NK cell receptors natural killer
group 2D (NKG2D) and natural cytotoxicity receptors
(NCR) [37]. However, ethanol extracts of the mycelium from
the same mushrooms inhibited the expression of these mol-
ecules by the same NK cells [37]. These findings support the
notion that the mode of extraction of medicinal mushrooms
may influence the immunomodulatory effects of the mush-
rooms on NK cells [37]. The possible effects of AHCC® on
NK cells of humans and mice were reported in different
clinical settings including infections and malignancies. In
human studies, AHCC® was orally administered at 3 g a
day while most mouse studies used oral AHCC® in a range
of 0.1-0.48 g/kg/day, except two studies where the doses
were 1 and 3 g/kg/day, respectively. In the latter study,
AHCC® was evaluated for colitis in mice. It is noticeable
that 0.1-0.48 g/kg/day of AHCC® in mice is equivalent to
0.0081-0.039 g/kg/day of AHCC® in humans based on the
guidance of the US FDA [38, 39]. These doses are similar
to the recommended AHCC® doses of 1-3 g a day (0.017-
0.05 g/kg/day based on weight 60 kg) for humans. The find-
ings from these studies are summarized in the following
sections (see also Table 1).
2.1. Infections. Influenza virus is one of the most significant
viral infections that causes substantial mortality and morbidity
Table 1: The effects of AHCC® on natural killer (NK) cells in health and disease.
Host Condition AHCC®
supplementation dose Effects Reference
Mice Influenza viral
infection (H1N1)
∗Oral, 1 g/kg/day
∗∗(25 mg/day)
Increased NK cell percentage and activity
Improved survival, lung integrity, and viral titers [24]
Mice Influenza viral
infection (H1N1)
∗Oral, 0.1 g/kg/day
∗∗(2.5 mg/day)
Increased NK cell lytic efficiency
Improved survival with enhanced
viral clearance
[22]
Mice Melanoma
∗Oral, 12 mg/day
∗∗(0.48 g/kg/day)
Increased NK cell number
Increased γδT cell number
Increased tumor antigen-specific CD8
+
T cells producing IFN-γ
Delayed melanoma development
[16]
Mice Melanoma
∗Oral, 10 mg/day with or
without i.p. CpG ODN
∗∗(0.40 gm/kg/day)
Decreased melanoma development (size)
in mice treated with AHCC® alone or
AHCC® and CpG ODN
No immune cells analyzed
[18]
Mice Hepatoma
∗Oral, 0.36 g/kg/day
With 5-FU
∗∗(9 mg/day)
Increased NK cell percentage
Increased CD4
+
T cell percentage
Potentiate the effect of 5-FU on tumor
weight, size, and by AHCC®
[13]
Humans Cancers (open
label observational) Oral, 3 g/day Enhanced NK cell activity [17]
Humans
Healthy volunteers:
a double-blind,
placebo-controlled
Oral, 3 g/day or placebo No difference in NK cell activity between
AHCC® and placebo groups [26]
∗Dose used in each study. ∗∗Dose in g/kg/day was converted to dose in mg/day or vice-versa based on mouse weight of 25 g.
2 Journal of Immunology Research

in older adults, children, and immune-compromised hosts
[40]. The effect of AHCC® on influenza viral infection has
been studied, showing the possible beneficial effect, especially
through affecting NK cells [24]. Supplementing mice orally
with AHCC® (1 g/kg/day) improved survival and lung integ-
rity upon intranasal challenge with influenza virus (H1N1)
[24]. The mice that received AHCC® had increased NK cell
percentages and activity as measured against YAC-1 target
cells, along with decreased viral titers in the lungs [24]. The
former finding could be a potential mechanism responsible
for the beneficial effect of AHCC® in this mouse model in that
NK cells were suggested to have a role in controlling influenza
viral infection by secreting cytokines and expressing cytotoxic
molecules [30]. The improvement of survival with enhanced
viral clearance and NK cell lytic efficiency was also found in
influenza virus-infected mice which were supplemented with
a low-dose AHCC® (0.1g/kg/day) [22]. Of note, a transient
deficiency of NK and T cells was found in patients with severe
H1N1 influenza [41]. Given the increased NK cells in mice
treated with AHCC® [24], it would be intriguing to test
whether AHCC® could increase NK cells in patients with
H1N1 influenza. The effect of AHCC® can be beyond H1NI
influenza. The survival benefit by AHCC® supplementation
was observed in mice infected with avian (bird) influenza virus
H5N1 which could infect humans and poultry although its
mechanism is yet to be demonstrated [15]. In fact, the mortal-
ity rate of H5N1 avian influenza is much higher than that of
past influenza pandemics, reaching up to 60% [42]. The avail-
able data support the implication of NK cells in controlling
influenza virus via promoting the number and function of
NK cells, raising the possible consideration of exploring the
clinical utility of AHCC® for influenza viral infections, includ-
ing avian influenza infection, in humans.
2.2. Malignancies. The immune system, which plays an
essential role in the development and control of malignan-
cies, can become tolerant to tumor cells by multiple mecha-
nisms [36]. Different modalities such as cytokines and food
supplements have been considered to boost NK cell immu-
nity in treating cancers [3, 36]. Indeed, studies reported the
possible beneficial effects of AHCC® supplementation in
controlling cancers, especially in a combination with other
anticancer therapies like chemotherapy [23]. NK cells appear
to be involved in providing such effects. In an observational
study without a placebo control, AHCC® supplementation
(3 g/day) enhanced NK cell activity in a small number of
patients with various cancers including the prostate [17].
Also, the possible role of AHCC® in suppressing the develop-
ment of melanoma and immune mechanisms involved in
this process was studied. In fact, antitumor immunity is crit-
ical in controlling melanoma as evidenced by the recent
introduction of immunotherapies specifically enhancing T
cell function through blocking inhibitory check point mol-
ecules expressed on T cells [43, 44]. In a mouse model of
melanoma, AHCC® significantly delayed tumor develop-
ment after B16-F0 melanoma inoculation [16]. This phe-
nomenon was accompanied by an increase in the number
of NK cells, tumor antigen-specific CD8
+
T cells producing
IFN-γand gamma delta T cells [16]. The beneficial effect of
AHCC® on murine B16 melanoma is further supported
by a recent study reporting decreased melanoma sizes in
mice supplemented with AHCC® with or without CpG-
oligodeoxynucleotide (ODN), which is known to activate
innate immunity and serve as an immunologic adjuvant
[18]. The antitumor effects of low-dose 5-fluorouracil (5-FU)
were potentiated by AHCC® in hepatoma 22 tumor-bearing
mice through modulation of immune function, including
increased percentages of NK cells [13]. However, no signifi-
cant difference in NK cell activity was found between healthy
human volunteers who took AHCC® (3 g/day × 4 weeks)and
placebo, which could be related to small sample sizes
(n=10and 11 for AHCC® and placebo groups, respectively)
[26]. Given the potential effects of AHCC® on the number
and function of NK cells that play an essential role in
immune surveillance against malignancies, further human
and animal studies on NK cell-mediated anticancer effects
of AHCC® are warranted.
3. Effects of AHCC® on T Cell Immunity in
Infections, Inflammations, and Malignancies
3.1. T Cell Immune Responses. T cells, a component of the
adaptive immunity, play a critical role in defending hosts
against microorganisms and malignancy [29]. CD4
+
T cells
are T helper (Th) cells with the capacity to promote the func-
tion of other immune cells such as B cells and macrophages
by secreting cytokines and expressing costimulatory mole-
cules [45, 46]. CD8
+
T cells, which are cytotoxic T cells armed
with the cytotoxic molecules perforin and granzymes, can kill
infected or tumor cells [47]. Mushroom extracts, especially
polysaccharides, are reported to promote immune responses
to tumor by affecting the functions of T cells and other
immune cells [3]. Oligosaccharides are the most abundant
component of AHCC® accounting for about 74% of its dry
weight [6] [7]. Indeed, the effects of AHCC® on T cell immu-
nity are observed in humans and animals (see Table 2 for
summaries). In human studies, AHCC® was orally adminis-
tered at 3 g a day (0.05 g/kg/day based on 60 kg weight), while
most mouse studies used oral AHCC® in a range of 0.36-
1 g/kg/day, which is equivalent to 0.029-0.081 g/kg/day of
AHCC® for humans based on the guidance of the US FDA
[38, 39]. In an observational study of healthy adults aged 50
or older, AHCC® supplementation (3 g/day for 60 days)
increased the frequency of peripheral CD4
+
and CD8
+
T cells
producing IFN-γand/or TNF-αat 30 and 60 days of ELCM
supplementation compared to the baseline [28]. Such a find-
ing was still noticed at 30 days after discontinuing AHCC®.
However, additional studies are necessary to determine the
effect of AHCC® on other T cell functions. The effects of
AHCC® on T cells could be mediated by affecting innate
immune cells since oligosaccharides including α-glucans
and β-glucans are known to stimulate innate immune cells
such as monocytes, macrophages, and dendritic cells that
can modulate the activation and differentiation of T cells
[5, 48–51]. We recently reported the promotion of Th 1
and 17 cells, which predominantly produced IFN-γand IL-
17, respectively, by AHCC® through inducing IL-1βproduc-
tion from monocytes in humans [20]. In accordance with this
3Journal of Immunology Research

finding, the culture supernatants of AHCC®-treated murine
monocytic J744.2 cells promoted the production of TNF-α
from splenic T cells of mice [12] while AHCC® induced
IL-8 production from human myelocytic THP-1 cells via
activating mitogen-activated protein kinases (MAPKs) and
NF-κB pathways [14]. In a mouse study, AHCC® administra-
tion increased cytokine production in the intestine fluid
dependently of TLR2 and TLR4, suggesting the implication
of these molecules in AHCC®-mediated immune modulation
[52]. Also, an increase in the number of circulating dendritic
cells (DCs) was found in healthy adults after receiving
AHCC® (3 g/day × 4 weeks), suggesting the possible implica-
tion of AHCC® in promoting immune responses via modu-
lating DCs [26]. Overall, the data support that AHCC® can
modify T cell immunity in part by activating innate immune
cells with the capacity to promote T cell activation.
3.2. Infections, Inflammations, and Malignancies. The possi-
ble effects of AHCC® on T cell immunity may have biological
significance in developing immune responses to antigens.
This is evidenced by a study reporting increased NKT cells
and CD8
+
T cells along with increased protective antibody
titers to influenza B in healthy people who received influenza
vaccine and AHCC® supplementation (3 g/day × 3 weeks)
[25]. Also, in a mouse model of West Nile encephalitis, mice
supplemented with AHCC® (600 mg/kg every other day) had
the expansion of γδT cells, which had an important role in
controlling West Nile virus infection, along with decreased
viremia [27]. The potential beneficial effects of AHCC® on
the immune system and bacterial infection were previously
reported in the hindlimb unloading mouse model of space
flight conditions which could adversely affect the immune
system [9, 10, 53]. Indeed, a recent study using the same
mouse model showed a trend towards increased T cell prolif-
eration in mice supplemented with AHCC® compared to
control mice [54].
The effect of AHCC® on CD4
+
T cells was found in hep-
atoma 22 tumor-bearing mice [13]. Compared to mice
treated with 5-FU, mice treated with 5-FU and AHCC® had
an increase in the percentage of CD4
+
T cells and levels of
Table 2: The effects of AHCC® on T cells in health and disease.
Host or origin
of cells Condition AHCC®
supplementation dose Effects Reference
Mice In vitro 100 μg/mL
Promoted the production of TNF-αby splenic
T cells by inducing IL-1 from murine monocytic
J744.2 cells
[12]
Mice
West Nile virus
infection in young
and old mice
∗Oral, 0.6 g/kg
every other day
∗∗(15 mg every
other day)
Increased γδT cells
Decreased viremia
Decreased mortality in young but not old mice
[27]
Mice Hepatoma
∗Oral, 0.36 g/kg/day
With 5-FU
∗∗(9 mg/day)
Increased CD4
+
T cell percentage and circulatory
IL-2 levels
Potentiate the effect of 5-FU on tumor weight,
size, and by AHCC®
[13]
Mice
A hindlimb unloading
mouse model of
space flight conditions
∗Oral, 1 g/kg/day
∗∗(25 mg/day)
Trend towards increased T cell
proliferation not reaching the level
of statistical significance
[54]
Mice Lymphocyte-driven
colitis model
∗Oral, 75 mg/day
∗∗(3 g/kg/day)
Decreased STAT4 phosphorylation in splenic CD4
+
T cells
Decreased colitis
[21]
Humans Healthy volunteers
age 50 or older Oral, 3 g/day Increased frequency of CD4
+
and CD8
+
T cells
producing IFN-γand/or TNF-α[28]
Humans In vitro 500 μg/ml
Promoted the production of IFN-γand IL-17 by
CD4
+
T cells by inducing IL-1βproduction
from monocytes
[20]
Humans
Healthy adults
receiving influenza
vaccination
Oral, 3 g/day
Increased CD8
+
T cells
Increased NKT cells
Increased protective antibody titers to influenza
B strain after influenza vaccination
[25]
Humans In vitro 250-500 μg/ml
Decreased IL-10, IL-17, and IFN-γproduction
from purified CD4
+
T cells stimulated with
anti-CD3 and CD28 antibodies
No effect on proliferation and survival
No change in FOXP3 expression
Kang et al.,
unpublished
observations
∗Dose used in each study. ∗∗Dose in g/kg/day was converted to dose in mg/day or vice-versa based on mouse weight of 25 g.
4 Journal of Immunology Research

IL-2, the T cell growth factor, in peripheral blood [13]. This
observation raises the possibility that the antitumor effect
of AHCC® can be mediated in part by modulating T cell
function. The immune system, including T cells, can
become tolerant to tumor cells by multiple mechanisms
[36]. Probably, the best-known mechanism is suppressing
T cell activation and effector function by triggering inhibi-
tory checkpoint molecules, including CTLA-4 (cytotoxic T
lymphocyte-associated antigen 4) and PD-1 (programmed
cell death protein 1), expressed on T cells [43, 44]. Immu-
notherapy targeting these molecules has made substantial
impacts in oncology by improving the survival of patients
with cancers such as non-small cell lung cancer, bladder
cancer, and melanoma [32, 44]. However, the effects of
mushroom extracts on inhibitory checkpoint molecules in
T cells are largely unknown.
Although the exact mechanism of how AHCC® affects T
cells is yet to be demonstrated, AHCC® can promote T cell
function through activating innate immune cells especially
with oligosaccharides like other mushroom extracts [3, 12,
14, 20, 26]. A recent study reported that AHCC® supplemen-
tation (75 mg/day) improved lymphocyte-driven colitis in
recombination activating gene 1- (RAG-1-) deficient mice
transferred with CD4
+
CD62L
+
T cells [21]. In this study,
the production of IL-6, IL-17, and IL-10 by mesenteric lymph
node cells as well as STAT4 phosphorylation in splenic CD4
+
T cells were decreased in colitis mice supplemented with
AHCC®. Of note, we noticed the suppression of cytokine
production from human CD4
+
T cells activated with anti-
CD3 and CD28 antibodies in vitro in the presence of AHCC®
(Kang et al., unpublished data). This suppressive effect of
AHCC® appeared to be greater on IL-10, IL-17, and IFN-γ.
However, AHCC® did not affect the proliferation and sur-
vival of human CD4
+
T cells activated with anti-CD3 and
CD28 antibodies. We also determined the effect of AHCC®
on the transcription factor FOXP3 that is highly upregulated
in T cells with regulatory function [29]. No effect of AHCC®
on FOXP3 expression in human CD4
+
T cells was noticed
(Kang et al., unpublished data). As aforementioned, since
AHCC® can promote T cell function by activating innate
immune cells, it is possible that the effects of AHCC® on T
cells could depend on the context of immune activation.
For instance, AHCC® could directly suppress cytokine pro-
duction from activated T cells while the function of T cells
may be promoted by innate immune cells in the presence
of AHCC®.
4. Conclusions
AHCC®, which is an extract from the culture of shiitake
(Lentinula edodes) mycelia, has a broad range of effects on
the immune system including NK and T cells. Such effects
could be executed by directly modulating the numbers and
functions of these cells as well as by affecting the function
of monocytes, macrophages, and DCs with the capacity to
promote T cell function. Plus, the effects of AHCC® on NK
and T cells appear to have biological implications as sug-
gested by the results of clinical studies and in vivo animal
studies on infections, inflammations, and tumors. Studies
exploring additional immunologic effects of AHCC® and
mechanisms underlying these effects in health and disease
are warranted. Of note, the intestinal microbiome has been
a subject of intensive investigations in the field of food sup-
plements and medicinal foods including extracts of mush-
rooms. However, the effects of AHCC® on the intestinal
microbiome is unknown. The results of such studies explor-
ing the effects of AHCC® on the immune system and/or
microbiome would lead to advancing our understanding in
the utility of medical mushrooms including AHCC®, espe-
cially in the context of recently introduced immunotherapies
targeting inhibitory checkpoint molecules including CTLA-4
and PD-1.
Conflicts of Interest
Insoo Kang received unrestricted research funding from
Amino Up Co., Ltd., Sapporo, Japan, the manufacturer of
AHCC® that was discussed in this work, and is a consultant
of Amino Up Co., Ltd. Takahiro Maeda, Hiroshi Nishioka,
and Fujii Hajime are employees of Amino Up Co., Ltd.
Acknowledgments
This work was supported in part by an unrestricted research
fund from Amino Up Co., Ltd., Sapporo, Japan.
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