Immunomodulation Induced by Echinacea

Immunomodulation Induced by
Echinacea
Prof DR Dr Ariyanto Harsono SpA(K)

Ag
IL-12/ IL-1
TCR
MHC-IIT
h0
Th-2
IL-1
TNF-β, IFN-γ
IL-2, IFN-γ
B-Cell
IL-4
IL-5
SEL PLASMA SEL MEMORI
IL-6
IL-10
CTL
MHC-I
I L-2
IFN-γ
SEL-NK
SEL-NK AKTIF
FC-R
L
SEL ABNORMAL
SITOTOKSIN
SEL-LISIS
Sel Abnormal
Memory Cells
ADCC
Prof DR.dr. Ariyanto Harsono SpAK
FASL Th.1
Introduction

Dr. Ariyanto Harsono SpAK 3

B-T Cell Interaction

B-T Cell Interaction
Th1
IgG
IgM
IgA IL-12
IFN-g

INNATE iMMUNITY

INNATE Immunity,,,,,

IgA
TReg
TGF-b
Imunitas Humoral

IgG
Th1 Cell
Imunitas Humoral…..

IgG
Th1 Cell
Imunitas Humoral…..
CTL
DTH Prof DR.dr. Ariyanto Harsono SpAK
DNA /Whole cell Vaccine

Effectors mechanisms against extracellular pathogens
OPSONISATION
Bacteria in extracellular space
Fc receptor
binding
+
Ab
OPSONISATION Phagocytosis

Effectors mechanisms against extracellular pathogens
COMPLEMENT Activation
Bacteria in extracellular space
+
Ab &
COMPLEMENT
Lysis
Complement & Phagocytosis
Fc receptor binding
Opsonisation

Clinical Features of immune deficiency
• Syndromes
• Failure to Thrive
• Bacterial infection
• Viral Infection
• Opportunistic infection
• Chronic diarrhea
• Blood abnormality
• Skin lesions

MANAGEMENT
Hematopoietic growth factors
Methisoprinol
Echinacea
Interferon
propolis

History
• Native Americans may have used Echinacea for more
than 400 years to treat infections and wounds and as a
general cure-all
• Its use began to decline in the US after the introduction
of antibiotics
• Increasingly popular in Germany throughout the 20th
century. Most of the scientific research on Echinacea
has been conducted in Germany
• Today, people use Echinacea to shorten the common
cold and reduce symptoms, such as sore throat, cough,
and fever
Am Fam Phycisian 2003;67:77-80
Univ of Maryland Medical Center
Wikipedia, the free encyclopedia

• Native to eastern and central North America
• echinos is Greek for hedgehog
• Named for the prickly scales in its large conical seed head,
resembles the spines of an angry hedgehog

Active constituents
• Vary slightly according to species and include
caffeic acid derivatives (primarily echinocoside),
flavonoids, essential oils, polyacetylenes,
alkylamides, and polysaccharides
• No single constituent has been found to be
primarily responsible for Echinacea's immune-stimulating
effect; rather they appear to all work
together to accomplish this
Alternative Medicine Review 2001

General uses
• Several laboratory and animal studies suggest that
Echinacea contains active substances that enhance
the activity of the immune system
• Many herbalists recommend Echinacea to help
boost the immune system and help the body fight
infections
• Other functions: relieve pain, reduce inflammation,
and have hormonal, antiviral, and antioxidant effect
Wikipedia, the free encyclopedia

Echinacea
Pharmacodynamic of Echinacea is:
o Stimulates lymphokine production by limphocyte, increases TNF-a, IL-1,
IL-6, IL-10,
o Enhances cellular immunity in healthy children or immunodeficiency,
increases NK cell activity, and inhibits hialuronidase.
o Echinacea works especially in non specific immune system.
o Evidence until recently there is no disadvantage in long-term use, and
does not aggravate asthma and auto-immune disease.
o Enhancing phagocytosis of granulocyte of human in vitro.
o Increases phagocytosis of candida albicans by granulocyte and monocyte,
as well as increases leukocytes count: granular, neutophile and
macrophage.
IMMUNO-POTENTIATOR

A total of 26 controlled clinical trials (18 randomized, 11
double-blind) were identified; 6 of these involved
testing three different mono-extracts, and 20 involved
testing three different preparations also containing
other ingredients. Nineteen trials studied the efficacy of
the prophylactic or curative treatment of infections; 4
trials the reduction of side-effects of antineoplastic
therapies and 3 trials the modulation of various
laboratory immune parameters. The primary authors
claimed that 30 of the 34 treatment strategies showed a
superior efficacy to those of the control groups. The
methodological quality of most studies was low and
only 8 trials scored more than half of the maximum
possible score points.
Melchart D, Linde K, Worku F, Bauer R, Wagner H. Immunomodulation with echinacea — a systematic review of controlled clinical
trials. Phytomedicine 1994, 1: 245-254

Immunomodulation
Many studies investigating immunomodulatory
properties have been conducted with different
Echinacea species, extracts, and plant parts.
However, there is little agreement on which
chemical constituents are responsible for activity
on the immune system. Enhanced macrophage
function, stimulation of cytokine production
(including certain interleukins and tumor necrosis
factor alpha), enhanced natural-killer function, and
increased mean circulating total white blood cell
counts have all been demonstrated in vitro.

ANTI-INFLAMMATION ACTIVITY
Echinacea purpurea is one of the main medicinal
Echinacea species and have long been used to treat
infections, to aid in wound healing and to enhance the
immune system.
Alkamides and caffeic acid derivatives are potent anti –
inflammatory agents present in Echinacea . Echinacea-derived
alkamides have immunomodulatory and anti-inflammatory
activity. E. purpurea (EP) have been used
for wound healing, pain relief and alleviation of cold
symptoms. Alcohol extracts of Echinacea offers anti-inflammatory
effects through inhibition of production
of inflammatory mediators tumor necrosis factor-alpha
(TNF-α) and nitric oxide (NO).

Prostaglandin E2 (PGE2) is a critical inflammatory
mediator that is produced through the arachidonic
acid cascade. The anti-inflammatory role of
Echinacea is also mediated through own regulation
of cyclooxygenase-1 and cyclooxygenase-2 through
suppression of Prostaglandin E2 activation. COX-1
and COX-2 catalyze the reaction converting
arachidonic acid, released by phospholipase A, to
Prostaglandin E2. Wagner has reported
lipoxygenase- inhibiting anti-inflammatory activity
attributable to one of E. purpurea’s isobutylamides,
dodecatetraenoic acid.
.

Alcohol extracts of Echinacea are composed of two
classes of natural chemicals lipophilic alkamides
and water-soluble caffeic acid derivatives. Caffeic
acid derivatives have an antihyaluronidase activity.
An inhibition of hyaluronidase leads to
accumulation of enough hyaluronan in the
extracellular matrix for wound caffeic acid
derivative, showed a healing process characterized
by reduced inflammatory response and higher
hyaluronan content. These data indicate that
Echinacea presents a clear antiinflammatory
activity that may promote wound tissue recovery.

ANTI-OXIDANT ACTIVITY
Echinacea was found to be a very potent antioxidant38.
Arachidonic acid metabolism and prostaglandin E2
production were reduced by several E. purpurea. Alcohol
extracts of Echinacea are typically composed of two
classes of natural chemicals, lipophilic alkamides and
water-soluble caffeic acid derivatives. Caffeic acid
derivatives are effective antioxidants in free radical
generation systems and have an anti hyaluronidase
activity. Enhancement of free radical scavenging activity
has been shown by laboratories in the U.S. and Canada.
Hu and Kitts investigated anti-oxidant and free radicals
scavenging activity, including suppression of oxidation of
human low-density lipoprotein.
.

ANTI IMMUNOSUPPRESSANT
Echinacea products are the most popular herbal
immunostimulants in North America and Europe. In 1997
Echinacea may be best known as an immunostimulant. There
have been numerous reports of immunomodulatory properties
in various preparations derived from different parts of several
species of Echinacea. A series of studies in mice using purified
polysaccharides from Echinacea plant cell cultures showed a
stimulatory effect when applied to immune cells in culture or
injected intraperitoneally into mice. Mice with suppressed
immunity due to treatment with cyclophosphamide or
cyclosporin also had an increase in these immune functions
when given purified polysaccharides from Echinacea.

These studies suggest that Echinacea stimulates immune
functions in healthy or in immunosuppressed animals. These
immunologically active polysaccharides did not stimulate all
immune cells. B cells were not activated, nor did the B cells
produce more antibodies to sheep red blood cells.
Apparently, purified polysaccharides from E. purpurea act on
the nonspecific branch of immunity. Recent studies have
been shown that rhinoviruses could stimulate the
transcription of various immuneresponse genes in different
types of cells. Furthermore the expression of cytokine genes
and some of their secreted products in bronchial epithelial
cells could be reversed by Echinacea preparations. Several
animal and human studies have suggested that Echinacea
stimulates neutrophil and macrophage phagocytic function.
Other scientific studies suggests that the Echinacea purpurea
possesses nonspecific, short-term immune system stimulant
properties.

Anti Fungal
The Extract of E. purpurea has been shown to have antifungal
activities in a series of in vitro experiments testing activity
against various Candida species, and various Saccharomyces
cerevisiae, Candida albicans the most common fungal cause
of human skin disease. Antimicrobial actions were observed
in various E. purpurea root and herb extracts. Other
laboratories have also reported anti Candida activity of
extract of Echinacea purpurea. Phagocytosis of Candida by ex
vivo human macrophages and natural killer cells was found to
be enhanced following exposure to extracts of both E.
purpurea and Gingseng. Mouse macrophage activity against
Candida has also been observed to be stimulated by E.
purpurea polysaccharide exposure. The polysaccharide rich
Echinacea purpurea extract was found to decrease the
infection and death rates of immunosuppressed mice infected
with Candida.

Coeugniet and Kuhnast demonstrated a human
clinical trial testing an expressed juice of E. purpurea
(Echinacin®) for ability to effect recurrent vaginal
yeast infections.
They found Echinacin®-treated groups
demonstrated increased skin reactivity and
decreased recurrence of vaginal candidiasis over the
6-month monitoring period while 60% of controls
got new infections, only 5–17% of women in the
treatment groups were diagnosed with recurrent
vaginal infections (P < 0.05).

ANTI VIRAL ACTIVITY
Biological activity of the chemical Components of E.
purpurea have been characterized, Echinacea has
antiviral and anti bacterial activity and they have
found that cultured cells infected with virus and
exposed to E. purpurea juice demonstrated an
increased rate of presentation of viral antigen.
Benzalkonium chloride and phytochemicals derived
from Echinacea purpurea was found to have
antiviral activity against herpes virus in a human cell
model. Echinacea purpurea was also very effective
against influenza virus.

Skwarek et al revealed that the extract of E. purpurea has
been found to inhibit viral replication in animal cell viral
culture models. Eilmes demonstrated that complex has more
viral-infection- inhibititory activity fractions. Polysaccharide
derived from Echinacea purpurea has been shown to
stimulate macrophage activity and several functions related to
cytokine production and groups of phenolic compounds and
alkamides, which have demonstrated antiviral and antifungal
properties, respectively. These activities could be related to
the reports that some E. purpurea preparations were able to
prevent or control upper respiratory infections (URIs). Recent
study described a human trial testing the efficacy of Echinacea
in preventing colds induced by a cultured rhinovirus. There are
no reports on E.Purpurea in relation to HIV.

Immune stimulations
Echinacea's immune-stimulating properties are quite
complex and are attributed to the combined effect of
several of its constituents
• directly stimulated white blood cell production
•  phagocytic activity
•  NK cell activity
•  antibody-dependent cellular cytotoxicity,
•  tumor necrosis factor-alpha (TNF-a)
•  complement activity
•  cytokine production
•  enzyme: cyclo-oxygenase, lypo-oxygenase,
hyaluronidase
Alternative Medicine Review 2001
Infect Immune 1994:46:845-9

Uses & efficacy
• Upper respiratory
infection, prevention
• Upper respiratory
infection, treatment
• Urinary tract
infection
• Fungal infections

Acute respiratory infection
• Same (early) symptoms: fever, cough, coryza
• Upper – lower; nose – alveoli; AURI – ALRI
• Involving lower respiratory part – fast breathing &
difficult breathing
• fever, cough, coryza  symptoms of ARI due to
influenza virus:
Influenza like illness (ILI) /
influenza like symptoms /
influenza like syndrome

Precautions
• Herbs contain active substances that may trigger side
effects and interact with other herbs, supplements, or
medications
• In Germany, use of Echinacea is restricted to no longer
than eight weeks at a time
• Echinacea loses its effectiveness after eight consecutive
weeks regular users of this herb
• People with tuberculosis, leukemia, diabetes, connective
tissue disorders, multiple sclerosis, HIV or AIDS, any
autoimmune diseases, or, possibly, liver disorders should
not take Echinacea

Side effects & contraindications
• In rare cases, echinacea may cause allergic reactions
ranging from a mild rash to anaphylaxis
• People with asthma and allergies may be at an increased
risk for developing these adverse reactions
• When taken by mouth, echinacea may cause temporary
numbing and tingling on the tongue.
• Evidence suggests that the use of echinacea during
pregnancy does not increase the risk of birth defects or
other pregnancy-related health problems

Echinacea & pregnancy
positive
Pregnancy outcome following gestational exposure
to echinacea: a prospective controlled study.
The Motherisk Program, Division of Clinical Pharmacology
/Toxicology, The Hospital for Sick Children, University Ave,
Toronto, Canada
CONCLUSIONS: This first prospective study suggests
that gestational use of echinacea during organogenesis
is not associated with an increased risk
for major malformations.
Arch Intern Med. 2000 Nov 13;160(20):3141-3.

positive
Safety and efficacy of echinacea (E. angustafolia, e. purpurea and e. pallida) during
pregnancy and lactation.
Department of Clinical Pharmacology and Toxicology,
University of Toronto, Canada.
CONCLUSIONS: Echinacea is non-teratogenic when used
during pregnancy. Caution with using Echinacea during
lactation until further high quality human studies can
determine its safety.
Can J Clin Pharmacol. 2006 Fall;13(3):e262-
7.

positive
Conclusion: A recent Mother-risk study showed
that use of echinacea during the first trimester
of pregnancy was NOT associated with
increased risk of major malformations
Canadian Fam Phycisian 2001;47:1727-8

negative
Influence of Echinacea purpurea intake during pregnancy
on fetal growth and tissue angiogenic activity.
Dept. of Obstetrics and Gynecology,
Medical University of Warsaw, Poland.
Conclusion, there is some possibility that pharmaceuticals containing
Echinacea purpurea might influence fetal development in human also,
because they may interfere with embrional angiogenesis, and should not
be recommended for pregnant women.
Folia Histochem Cytobiol. 2007;45 Suppl 1:S35-9.

negative
Safety and efficacy of herbal remedies in obstetrics
- review and clinical implications.
Dept of Chemistry/Centre for Pharmacy, Univ of Bergen,
Allégaten 41, 5007 Bergen, Norway.
CONCLUSIONS: there is limited documentation on the safety and efficacy of
many herbs commonly used during pregnancy.
Midwifery. 2009 Sep 24.

Safety
• GI upset
• No aggravation of allergy
• US FDA category ©
Prof DR.dr. Ariyanto Prof DR.dr. Ariyan tHoa Hrsaornsoon Sop ASpKAK

Ag
IL-12/ IL-1
APC MHC-II Th0
Conclusion
Th-2
Th.1
IL-1
TNF-β, IFN-γ
IL-2, IFN-γ
B-Cell
IL-4
IL-5
SEL PLASMA SEL MEMORI
IL-6
IL-10
CTL
MHC-I
I L-2
IFN-γ
SEL-NK
Sel Abnormal FASL
SEL-NK AKTIF
FC-R
L
L
SITOTOKSIN
SEL ABNORMAL
SEL-LISIS
Memory Cells
ADCC
Echinacea

REFERENCES
1. McGregor RL, The taxonomy of the genus Echinacea (Compositae). University of
Kansas Science Bulletin, 48:113–142, (1968).
2. Binns SE, Baum BR and Arnason JT, A taxonomic revision of Echinacea
(Asteraceae: Heliantheae). SystBot, 27:610–632, (2002a).
3. Foster S, “Echinacea: Nature’s Immune Enhancer”. Rochester, VT: Healing Arts
Press, (1991).
4. Bauer, R. and H. Wagner. Echinacea species as potential immunostimulatory
drugs. In:H. Wagner and N.R. Farnsworth (eds.), Economic and medicinal plant
research.Vol. 5. Academic Press, New
York, 1991, p. 253–321.
5. Brevoort P, The Booming U.S. Botanical Market: A New Overview. HerbalGram,
44:33–46, (1998).
6. B. Galambosi. Cultivation in Europe. In: S.C. Miller and H. Yu (eds.), Echinacea:
The genus Echinacea, CRC Press, Boca Raton, Fla., 2004, pp. 29–52.
7. W. Letchamo, L.V. Polydeonny, N.O. Gladisheva, T.J. Arnason, J. Livesey, and
D.V.C. Awang. Factors affecting Echinacea quality. In: J. Janick and A. Whipkey
(eds.), Trends in new crops and new uses, ASHS Press, Alexandria Va, 2002, pp.
514–521

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