REVIEW ARTICLE

Iran J Allergy Asthma Immunol

June 2012; 11(2): 111-119.

Herbal Medicines for Immunosuppression

Zahra Amirghofran

Immunology Department, Medicinal & Natural Products Chemistry Research Center and
Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Received : 8 July 2011 ; Received in revised form: 28 August 2011 ; Accepted: 15 September 2011

ABSTRACT

Herbal medicines have been used for centuries to treat different illnesses. Among more
than 20,000 herbal medicines available for humans, a limited number have sufficiently been
studied and numerous remained to be investigated for their efficacy in treating human diseases.
A number of herbal products are in use for their immunosuppressive effects. This capacity
of herbs may have useful applications in immune-mediated disorders including autoimmune
diseases and organ transplant rejection. Plants such as Salvia miltiorrhiza and Tripterygium wilfordii
has been shown to reduce inflammatory cytokines and mediators, indicating their value in the
treatment of acute graft rejections and autoimmunity. Tanacetum parthenium inhibits the release
of pro-inflammatory mediators from macrophages and lymphocytes and Curcuma longa down
regulates the expression of cytokines and chemokines as well as the transcription factor NF-
kappaB. There has been growing interest to investigate novel anti-inflammatory or
immunosuppressive activities from various sources particularly herbal medicines.
This review focuses on the plants that have recently received more attention regarding their
influence on the immune system, being reported as immunosuppressive and anti-inflammatory
agents and promising protective effects for immune-mediated diseases.

Keywords: Herbal medicines; Immunosuppression

INTRODUCTION effects, and there is an increasing need to find new drugs

with fewer side effects.
A number of herbal medicines have shown useful In reviewing the recent literature, this article discusses the
biological and pharmacological activity, including immunosuppressive potentials of several plants.
immunosuppressive effects. Immunosuppression using Before our discussion of the herbal medicines,
herbal products can provide an alternative to conventional we provide a brief review of the immune system and
chemotherapy, particularly since some chemical current synthetic immunosuppressive drugs.
immunosuppressive drugs have shown various adverse
The Immune System
Corresponding Author: Zahra Amirghofran, Ph.D; The human immune system has a fundamental role
Department of Immunology, Medical School, Shiraz University of in protecting the body against the pathogenic microbial
Medical Sciences, 71345-1798, Shiraz, Iran. Tel/Fax: (+98 711) 2351
575, 2359847, E-mail: [email protected] agents. This system is mediated by leukocytes that
derive from precursors in the bone marrow and develop

Copyright© 2012, IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY. All rights reserved. 111
 Z. Amirghofran

under the influence of cytokines and growth factors. Synthetic Immunosuppressive Drugs
The immune-committed cells recognize antigens Immunosuppressive drugs comprise a large number
trapped in the peripheral lymphoid tissues and are then of drugs that by different mechanisms of action can
activated. B cells produce antibodies that serve as modulate the immune system. Glucocorticoids are the
receptors for antigens and can bind to pathogens to most common of these drugs, and are widely used for
prevent or neutralize infection. T cells recognize the management of inflammatory diseases. These drugs
antigen on the surface of antigen-presenting cells inhibit various immune functions by affecting gene
(APCs) e.g., dendritic cells (DCs) and secrete cytokines transcription events.7,8 They mediate their actions by
which determine the differentiation of T helper (TH) binding to intracellular receptors, resulting in altered
and B lymphocytes.1 The TH response involves the protein-protein interactions and consequently
activation of macrophages and cell-mediated immunity regulation of gene expression.9 Cyclophosphamide is
and also affects immunoglobulin differentiation and another immunosuppressive drug, which affects mainly
antibody secretion and therefore humoral immunity.2 B cells. This alkylating agent is currently used to treat
TH cells after recognizing the antigen proliferate and diseases in which autoantibodies play a pathogenic
differentiate to specific lineages according to the local role, such as rheumatoid diseases.10 Depending on the
cytokine environment, either TH1 or TH2 cells, each of dosage and timing of administration,
which secretes certain cytokines. TH1 cells secrete cyclophosphamide can also affect T cells.11
cytokines interleukin (IL)-2, interferon (IFN)-γ and Cyclosporin A and FK-506 belong to the group of
tumor necrosis factor (TNF)-α, whereas TH2 kinase and phosphatase inhibitors. These drugs, after
lymphocytes secrete IL-4, IL-5 and IL-10. Recently binding to a specific immunophillin inhibit calcineurine
two novel subsets of CD4+ T cells including TH17 and which play a key role in the transcription of cytokines
regulatory T cell (Treg) were also identified. "Each (particularly IL-2) and T cell activation.12 They also
phenotype of T cells is characterized by unique inhibit the JNK and p38 cascades linked to the T cell
signaling pathways and expression of specific receptor.13 Various other immunosuppressive drugs
transcription factors, notably T-bet for TH1, GATA-3 have been developed with inhibitory effects on de novo
for TH2, forkhead box P3 (FoxP3) for Tregs and purine synthesis, including 6-mercaptopurine,
receptor-related orphan receptor (ROR) alpha and azathioprine, mizorbine and mycophenolate motefil
RORgammat for TH17 cells".3 Altered T cell responses (MMF). Azothioprine acts on the S-phase of the
and impaired regulatory function of the immune system cellular cycle and MMF acts specifically on inosine
play a major role in development of inflammatory and monophosphate dehydrogenase.14 Leflunomide is an
autoimmune diseases, such as multiple sclerosis and example of drugs with inhibitory effects on pyrimidine
rheumatoid arthritis.4 A number of anti-inflammatory nucleotide synthesis. The main mechanism of action of
drugs including various traditional medicines and these drugs is inhibition of dihydroorotate
natural products are being under study for the treatment dehydrogenase and subsequent suppression of
of various disorders. The effects of drugs on the lymphocyte proliferation. These synthetic drugs can be
immune system can be assessed by in vitro testing T distinguished from the large number of reagents
cell- mediated immunity in the presence of an antigen (including monoclonal antibodies) that have been
or mitogen. T cell stimulation by these molecules produced for immunosuppressive applications.15
initiates a cascade of events and gene expression, Despite the effectiveness of these various
which induce the resting T cells to enter the cell cycle, immunomodulating drugs in reducing immune
then proliferate and differentiate.5 This process trigger function, a major concern in recommending these drugs
proliferation signals which in turn lead to the activation for therapeutic purposes is their side effects.16-18
of certain transcription factors, synthesis of proteins Glucocorticoids have various side effects, particularly
and secretion of cytokines. General functioning of the when used at high doses for prolong periods.19
T cells in various inflammatory diseases can be Methabolic, gastrointestinal, cutaneous, neurological,
examined in different animal models, e.g. experimental musculoskeletal and ophthalmologic adverse effects
autoimmune encephalomyelitis (EAE) as a model of have been associated with long-term
19
multiple sclerosis and collagen-induced arthritis as a glucocorticosteroid therapy. Among the side effects
model of rheumatoid arthritis.6 of cyclophosphamides are gonadal toxicity, leukopenia

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 An Update on Medicinal Plants with Immunosuppressive Effects

as well as mutagenicity and increased risk of EAE has been recently investigated. The treatment of
developing cancer.19 Due to these effects, the discovery Lewis rats with curcumin significantly reduced both the
and recognition of safer new drugs without severe clinical severity of EAE, and leukocyte infiltration in
adverse effects has become a major goal for the spinal cord. A decrease in the IL-17, TGF-β, IL-6,
experimental medicine. and IL-21 mRNA expression as well as STAT3 and
RORgammat expression in curcumin-treated rats
Immunosuppressive Effects of Herbal Medicines indicated that the usefulness of curcumin in EAE
The capacity of herbal medicines to inhibit cellular treatment was mainly due to inhibition of TH17 cells
and humoral immune responses can have useful differentiation.24 Several clinical trials indicate
applications in some immune-mediated disorders curcumin may have potential as a therapeutic agent in
including autoimmune diseases.20 Both activation of T diseases such as inflammatory bowel disease,
and B lymphocytes and macrophages and defective pancreatitis, arthritis, and chronic anterior uveitis.25
apoptosis of immune effector cells play critical roles in The effect of this compound on B cell activation has
the pathogenesis of these disorders.21,22 There is an also been studied. Curcumin at high doses reduced the
ever-increasing interest in research on different plant proliferation of B cells stimulated with the Toll-like
species to document their therapeutic applications. receptor (TLR) ligands LPS and CpG
Various studies have investigated the oligodeoxynucleotides26 and at low doses enhanced
immunosuppressive effects of herbal medicines antibody responses indicating that curcumin could be a
growing in different parts of the world. We review strong modulator of B cell activation.26
some of the herbs that have recently received more
attention regarding their inhibitory influence on the Tripterygium Wilfordii Hook F
immune system below. The "thunder god" vine, Tripterygium wilfordii
Hook F (TWHf) growing in southern China, has been
Curcuma Longa extensively used to treat autoimmune diseases such as
Curcuma longa (Zingiberace), a perennial plant systemic lupus erythematosus and rheumatoid arthritis.
native to tropical South Asia, has been extensively TWHf (Celastraceae) not only inhibits mitogen-
utilized in folk medicine for treatment of infections and stimulated lymphoproliferation, but its active
inflammatory diseases. Turmeric, the bright yellow derivatives have also been shown to inhibit production
pigment extracted from the tuberous rhizome of this of proinflammatory cytokines by monocytes and
plant has been shown to inhibit the activation of human lymphocytes, as well as PGE2 production via the
DCs in response to inflammatory cytokines. Treatment cyclooxygenase pathway.27 In a recent clinical trial, the
of DCs with turmeric also inhibited the ability of DCs clinical efficacy of this plant versus sulfasalazine for
to stimulate the mixed lymphocyte reaction (MLR).23 the treatment of patients with symptomatic rheumatoid
The main biological effects of turmeric have been arthritis was demonstrated.28 There are both laboratory
attributed to curcumin, a major curcumanoid found in and clinical data showing significant beneficial
turmeric. This naturally occurring polyphenolic immunosuppressive effects of the derivatives of this
phytochemical is a strong anti-inflammatory and herb.27 Triptolide, a diterpenoid component isolated
antioxidant agent which can change the expression of from TWHf has been shown anti-inflammatory and
various transcription factors, cell cycle proteins, and immunosuppressive activities by its inhibitory effect on
signal transducing kinases. Curcumin has been shown T-cells. The effect of triptolide on induction of oral
to be active on lymphocytes and affect on a series of tolerance in the Peyer's patch as important site of
immunological functions including antigen mucosal immune responses has also been studied. This
presentation, humoral and cell-mediated immunity, and compound by lowering CD4+ and CD8+ cells in the
cytokine production.24 This compound can inactivate Peyer's patch and the CD4+ cells in periphery reduced
the transcription factor NF-kappaB and by this function arthritis severity in a model of experimental
down regulates the secretion of a variety of inflammatory polyarthritis.29
proinflammatory cytokines and chemokines.25 The effect of triptolide on the TH17 cells that are
Considering the strong anti-inflammatory effect of involved in the immunopathogenesis of various
curcumin, its efficacy and mechanism of action against autoimmune diseases has been investigated. This

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 Z. Amirghofran

compound significantly inhibited the generation of TH17 Danshen), widely used to treat hepatitis, heart and brain
cells from murine splenocytes and purified CD4+ T cells diseases.40,41 This plant has been shown to inhibit IL-12
in a dose-dependent manner and suppressed collagen- production in activated macrophages and IFN-γ
induced arthritis. The transcription of IL-17 mRNA and production in lymph node cells.42 IFN-γ production
IL-6-induced phosphorylation of STAT3 signaling may be a key therapeutic strategy for modulating
molecule was inhibited by triptolide.30 Triptolide immunological diseases dominated by TH1-derived
treatment in EAE caused a significant inhibition of the cytokine responses. These results may explain some
mRNA expression of both TH1/TH17 and TH2 known biological activities of this plant including its
cytokines in mononuclear cells as well as in spinal cord anti-inflammatory effect, and suggest its possible use in
tissues, indicating the protective effect of triptolide in the treatment of immunological diseases dominated by
this model.31 TH1-derived cytokine responses.42 In a clinical trial the
The immunosuppressive activity of TWHf has also usefulness of S. miltiorrhiza extract in treatment of
been shown in organ transplantation. In an in vivo rat patients with severe acute pancreatitis by reducing the
kidney transplant model, demethylzeylasteral (T-96), proinflammatory cytokines has been shown.43
isolated from this plant in combination with prednisone The major active component of Salvia miltiorrhiza is
significantly prolonged the survival of kidney- Tanshione IIA (TSN). TSN have been shown to reduce
transplanted rats,32 indicating the potential usefulness of inflammatory cytokines including IL-2, IL-4, IFN-γ and
TWHf bioactive compounds in the treatment of acute TNF-α, whereas increasing anti-inflammatory cytokine,
graft rejections and autoimmunity. IL-10. Considering the effect of this component on
reducing plasma alanin aminotransferase and aspartate
Glycyrrhiza Species amino transferase levels observed in mice with
Glycyrrhiza (liquorice) belonging to Fabaceae concanavalin A-induced immune-mediated liver injury,
family, has been grown for centuries in China, Africa, TSN has been suggested to be useful for liver injury
Europe, India and the Middle East. This plant is used for therapeutics.44
its antimicrobial, hepatoprotective, cardioprotective and
immunomodulatory properties in folk medicine.33 The Camellia Sinensis
inhibitory effect of flavonoids extracted from licorice on Green tea, a product of the dried leaves of Camellia
LPS-induced acute pulmonary inflammation in mice has sinensis (Theaceae), growing throughout Asia, Middle
been shown.34 Liquorices (Radix glycyrrhizae) have East and Africa, is a commonly consumed beverage in
been used for treatment of hepatitis. In this regard a the world. This products is used for many purposes in
component known as diammonium glycyrrhizinate (DG) folk medicine including as analgesic, cardiotonic,
was purified from liquorices that could prevent murine carminative, CNS-stimulant, digestive and diuretic. The
T-cell-mediated fulminant hepatitis.35 DG inhibited the polyphenolic compounds from green tea possess
recruitment of lymphocytes into the liver and protected antiinflammatory properties, in various experiments
hepatocytes from apoptosis through an IL-6-dependent using animal models its immunosuppressive effect have
way.35 In a pilot randomized open-label study, the effect been shown. Green tea reduced autoimmune symptoms
of a new emollient cream containing milk proteins and in the rat adjuvant arthritis, a model of human
Glycyrrhiza glabra extracts in patients with psoriasis was rheumatoid arthritis45 and in a murine model for human
demonstrated.36 Sjogren's syndrome.46
Liquorice root contains glycyrrhizin and the major In recent years, the attentions have been made on
metabolite of glycyrrhizin is Glycyhrritinic acid,37 which epigallocatechin-3-gallate (EGCG), a component of
has shown antiinflammatory effects in different animal green tea with anti-inflammatory and
models.38 The inhibition of calcineurin activity and T immunomodulatory activities.47 This compound has
cell proliferation by glycyrol from Glycyrrhiza uralensis shown inhibitory effects on human monocyte-derived
has also been reported.39 DCs and, consequently, on the T-cell-mediated immune
responses.47 EGCG has considerably suppressed brain
Salvia Miltiorrhiza inflammation and neuronal damage in EAE induced by a
Salvia miltiorrhiza (Labiatae) is a popular medicinal proteolipid protein.48
plant growing abundantly in China (locally called

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 An Update on Medicinal Plants with Immunosuppressive Effects

Tanacetum Parthenium plants grow in subtropical regions of Europe, Asia,

Tanacetum parthenium (Asteraceae) originally is Africa and America. Iran is the largest producer of this
native to Europe’s Balkan mountains, and now grows in plant in the world. Berbamine is a purified compound
different parts of the world. This plant, known under the from Berberis vulgaris and other Berberis species with
common name of feverfew, has been used as a folk strong anti-inflammatory properties in EAE model. In
remedy for rheumatoid arthritis and fever.49 The crude early studies, the inhibitory effects of berbamine on the
feverfew extract and its purified parthenolide can delayed type hypersensitivity reaction (DTH) and MLR
modulate adhesion molecule expression in human was shown.52 This compound also prolonged allograft
synovial fibroblasts.50 This species has shown the survival in skin-transplanted mice. Recently, study on
capacity to inhibit several pro-inflammatory enzymes the production of cytokines from CD4+ T cells treated
including 5-lipoxygenase, phosphodiesterase-3 and with berbamine has shown the selective inhibitory effect
phosphodiesterase-4. It also inhibits the release of pro- of this compound on STAT4 expression and production
inflammatory mediators nitric oxide, prostaglandin (PG) of IFN-γ in the cells, indicating the immunosuppressive
E2 and TNF-α from macrophages and IFN-γ and IL-4 effects of this compound.53
from human peripheral blood mononuclear cells.50 The Other plants
bioactive compounds of this plant have been suggested In various other studies, the capacity of herbal
to safely support the immunotherapy of colon cancer.51 medicines to suppress the immune response has been
studied,54-63 e.g. garlic has shown to reduce the
Berberis Species proinflammatory cytokines IL-1, TNF-α, and IL-8, and
Berberis species (Berberidaceae) are the plants with
long history of application in traditional medicine. These

Table 1. Various other medicinal plants with immunosuppressive effects

Plants Family Immunosuppressive effects Ref.

Campylotropis hirtella Leguminosa -Inhibits mitogen-induced splenocyte proliferation 64
Andrographis paniculata Acanthaceae -Relief of rheumatoid arthritis symptoms 65-67
-Inhibitory effects on NF-κB trans-activation activity
-Inhibits nitric oxide and prostaglandin E2
Bupleurum falcatum Umbelliferae -Inhibits the proliferation and activation of T cells through cell cycle 68-69
arrest and induction of apoptosis
-Inhibits T cell activation through the modulation of NF-kappaB
transcription factor
Clerodendron trichotomum Verbenaceae -Inhibits arachidonic acid release and prostaglandin E2 production 70-71
-Inhibits NF-κB dependent pathway in macrophages
Periploca sepium Asclepiadaceae -Suppresses IL-17 production and inhibits differentiation of Th17 cells 72-73
-Inhibits NKT-derived inflammatory cytokine productions
Artemisia vestita Compositae -Inhibits IFN-γ signaling 74-75
-Down-regulates the activation, adhesion and metalloproteinase
production of T lymphocytes
Salvia mirzayanii Labiatae -Inhibits lymphocyte proliferation 76-77
-Induce apoptosis in activated lymphocytes,
-Inhibits humoral and DTH response to SRBC in mice,
-Inhibits IL-2 production
Dracocephalum kotschyi Labiatae -Inhibits lymphocyte proliferation 78-80
-Induce apoptosis in lymphocytes
Argyrolobium roseum Papilionaceae - Down regulates Th1/Th2 cytokines release 81
- Decreased T cells and B cells numbers

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 Z. Amirghofran

Other plants Induction of interleukin-17 production by regulatory T

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