Immunomodulation Induced by Echinacea

Prof DR Dr Ariyanto Harsono SpA(K)

Ag

MHC-IITh0

IL-12/ IL-1

Th-2

IL-1

TNF-β, IFN-γ

IL-2, IFN-γ

B-Cell

IL-4

IL-5

SEL PLASMASEL MEMORI

IL-6

IL-10

CTL MHC-I

I L-2 IFN-γ

SEL-NK

SEL-NK AKTIFFC-R

L

SEL ABNORMAL

SITOTOKSIN

SEL-LISIS

Sel Abnormal

Memory Cells

ADCC

Prof DR.dr. Ariyanto Harsono SpAK

FASL Th.1

TCR

Introduction

Dr. Ariyanto Harsono SpAK 3Prof DR.dr. Ariyanto Harsono SpAK

B-T Cell Interaction

Prof DR.dr. Ariyanto Harsono SpAK

B-T Cell Interaction

Th1

IgG

IgM

IgA IL-12

IFN-γ

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

INNATE iMMUNITY

Prof DR.dr. Ariyanto Harsono SpAK

INNATE Immunity,,,,,

IgA

TReg

TGF−β

Prof DR.dr. Ariyanto Harsono SpAK

Imunitas Humoral

IgG

Th1 Cell

Prof DR.dr. Ariyanto Harsono SpAK

Imunitas Humoral…..

IgG

Th1 Cell

CTL

DTH Prof DR.dr. Ariyanto Harsono SpAK

Imunitas Humoral…..

DNA /Whole cell Vaccine

Fc receptorbinding

Effectors mechanisms against extracellular pathogensOPSONISATION

OPSONISATION Phagocytosis

Bacteria in extracellular space

Ab

+

Prof DR.dr. Ariyanto Harsono SpAK

Effectors mechanisms against extracellular pathogensCOMPLEMENT Activation

Ab & COMPLEMENT

+

PhagocytosisComplement &Fc receptor binding

Lysis

Opsonisation

Prof DR.dr. Ariyanto Harsono SpAK

Bacteria in extracellular space

Clinical Features of immune deficiency

• Syndromes• Failure to Thrive• Bacterial infection• Viral Infection• Opportunistic infection• Chronic diarrhea• Blood abnormality• Skin lesions

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

Prof DR.dr. Ariyanto Harsono SpAK

MANAGEMENT

Prof DR.dr. Ariyanto Harsono SpAK

Methisoprinol

Echinacea

Interferon

Hematopoietic growth factors

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

Am Fam Phycisian 2003;67:77-80

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

Am Fam Phycisian 2003;67:77-80

Univ of Maryland Medical Center

Wikipedia, the free encyclopedia

Echinacea

Pharmacodynamic of Echinacea is: o Stimulates lymphokine production by limphocyte, increases TNF-α, 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.

Prof DR.dr. Ariyanto Harsono SpAK

IMMUNO-POTENTIATOR

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

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.

ImmunomodulationMany 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 ACTIVITYEchinacea 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 ACTIVITYEchinacea 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 IMMUNOSUPPRESSANTEchinacea 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 FungalThe 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 ACTIVITYBiological 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 stimulationsEchinacea'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-α)• complement activity• cytokine production• enzyme: cyclo-oxygenase, lypo-oxygenase,

hyaluronidaseAm Fam Phycisian 2003;67:77-80

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

Am Fam Phycisian 2003;67:77-80

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

Univ of Maryland Medical Center

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

Univ of Maryland Medical Center

Echinacea & pregnancypositive

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.

Pregnancy outcome fol lowing gestational exposure to echinacea: a prospective controlled study.

Arch Intern Med. 2000 Nov 13;160(20):3141-3.

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.

Echinacea & pregnancypositive

Can J Clin Pharmacol. 2006 Fall;13(3):e262-7.

Safety and efficacy of echinacea (E. angustafolia, e. purpurea and e. pallida) during pregnancy and lactation.

Canadian Fam Phycisian 2001;47:1727-8

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

Echinacea & pregnancypositive

Echinacea & pregnancy negative

Influence of Echinacea purpurea intake during pregnancyon fetal growth and tissue angiogenic activity.

Dept. of Obstetrics and Gynecology, Medical University of Warsaw, Poland.

Folia Histochem Cytobiol. 2007;45 Suppl 1:S35-9.

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.

Echinacea & pregnancynegative

Dept of Chemistry/Centre for Pharmacy, Univ of Bergen, Allégaten 41, 5007 Bergen, Norway.

Midwifery. 2009 Sep 24.

Safety and eff icacy of herbal remedies in obstetr ics - review and cl inical implications.

CONCLUSIONS: there is limited documentation on the safety and efficacy of many herbs commonly used during pregnancy.

Safety

• GI upset• No aggravation of allergy• US FDA category ©

Prof DR.dr. Ariyanto Harsono SpAKProf DR.dr. Ariyanto Harsono SpAK

Ag

APC MHC-II Th0

IL-12/ IL-1

Th-2

Th.1

IL-1

TNF-β, IFN-γ

IL-2, IFN-γ

B-Cell

IL-4

IL-5

SEL PLASMASEL MEMORI

IL-6

IL-10

CTL MHC-I

I L-2 IFN-γ

SEL-NK

SEL-NK AKTIFFC-R

L

L

SEL ABNORMAL

SITOTOKSINSEL-LISIS

Sel Abnormal FASL

Memory Cells

ADCC

EchinaceaProf DR.dr. Ariyanto Harsono SpAK

Conclusion

REFERENCES1. 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, NewYork, 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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