Journal of Microbiology, Immunology and Infection (2012) 45, 165e184

Available online at www.sciencedirect.com

journal homepage: www.e- jmii .com

REVIEW ARTICLE

A review of immunomodulators in the Indiantraditional health care system

Dinesh Kumar a,*, Vikrant Arya b, Ranjeet Kaur c, Zulfiqar Ali Bhat a,Vivek Kumar Gupta b, Vijender Kumar a

aDepartment of Pharmaceutical Sciences, University of Kashmir, 190006 IndiabASBASJSM College of Pharmacy, Bela Ropar, Punjab 140111, Indiac Shoolini School of Pharmaceutical Sciences, Solan, Himachal Pradesh 173212, India

Received 14 April 2011; received in revised form 29 June 2011; accepted 12 July 2011

KEYWORDSCellular immunity;Humoral;Immunomodulators;Plant extracts;Traditional medicine

* Corresponding author. DepartmentUniversity of Kashmir, 190006 Jammu

E-mail address: sharmadinesh82@g

1684-1182/$36 Copyright ª 2012, Taiwdoi:10.1016/j.jmii.2011.09.030

Some of the medicinal plants valued in Ayurvedic Rasayana for their therapeutic potential havebeen scientifically investigated with promising results. A number of plant-based principleshave been isolated with potential immunomodulatory activity that can explain and justify theiruse in traditional medicine in the past and can form the basis for further research in the futureas well. The aim of this review is to highlight results of research done on immunomodulators ofplant origin. The selection of papers was made using the most relevant databases for thebiomedical sciences on the basis of their ethnopharmacological use. Many plants and somephytoconstituents responsible for immunomodulation have been explained. The review alsodiscusses biological screening methods for various plant drugs that focus on revealing themechanism involved in immunomodulation. This work shall hopefully encourage researchersto undertake further work on medicinal plants with potential immunomodulatory activity.Copyright ª 2012, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rightsreserved.

Introduction

According to the World Health Organization (WHO), aboutthree-quarters of the world population relies upon

of Pharmaceutical Sciences,and Kashmir, India.mail.com (D. Kumar).

an Society of Microbiology. Publ

traditional remedies (mainly herbs) for the health care ofits people. In fact, herbs and/or plants are the oldestfriends of mankind. They not only provided food and shelterbut also served to cure different ailments. Herbal medi-cine, sometimes called traditional or natural medicine, hasalways existed in one way or another in different culturesand civilizations, such as Ayurvedic (India), Egyptian,Western, Chinese, Kampo (Japan) and Greco-Arab or Unani-Tibb (south Asia). Traditional medicine all over the world is

ished by Elsevier Taiwan LLC. All rights reserved.

166 D. Kumar et al.

currently being revalued through extensive researchactivity on various plant species and their therapeuticproperties.

Ethnopharmacological activities in Ayurvedicmedicine

Ayurveda stresses the use of plant-based medicines andtreatments. Various plants identified in the Indian Ayurve-dic system of medicine display a wealth of pharmacologicalproperties. The ayurvedic system of medicine is one of theoldest systems of medicine and includes various ethno-pharmacological activities such as immunostimulation,tonic, neurostimulation, anti-ageing, antibacterial, anti-viral, antirheumatic, anticancer, adaptogenic, etc.1 Anentire section of the Materia Medica of Ayurveda is devotedto “Rasayana”, drugs reputed to enhance body resistance.2

Listed as a class in the texts of traditional Indian Medicineliterature, Rasayana consists of a number of plants reputedto promote physical and mental health, improve defensemechanisms of the body and enhance longevity. Theseattributes are similar to the modern concept of adapto-genic agents, which are known to afford protection of thehuman physiological system against diverse stressors.3 Anumber of medicinal plants as Rasayanas have beenclaimed to possess immunomodulatory activity, e.g.,Withania somnifera, Tinospora cordifolia, and Mangiferaindica.4,5 They can depress or potentiate the host’scapacity to resist infection and tumors non-specifically, orreact specifically to a foreign substance. Immunomodula-tors act on the complex network of mechanisms of theimmune system in a way not yet fully elucidated (Fig. 1).

Immunity

This may be defined as the body’s ability to identify andresist large numbers of infectious and potentially harmful

Figure 1. Immunomodulators in the lap of nature.

microorganisms, enabling the body to prevent or resistdiseases and inhibit organ and tissue damage. The immunesystem is not confined to any one part of the body. Immunestem cells, formed in the bone marrow, may remain in thebone marrow until maturation or migrate to different bodysites for maturation. Subsequently, most immune cellscirculate throughout the body, exerting specific effects.The immune system has two distinct but overlappingmechanisms with which to fight invading organisms, theantibody-mediated defense system (humoral immunity) andthe cell-mediated defense system (cellular immunity).6

Immune systemsThe basic architecture of the immune system is multilay-ered, with defenses on several levels. Most obvious andprimary is the skin: the first barrier against infection.Another is physiological, where conditions like thetemperature and pH of the body provide inappropriateliving conditions for foreign organisms. Once pathogenshave successfully entered the body, they are addressed bythe innate and/or the acquired or adaptive immune system.Both systems consist of a multitude of cells and moleculesthat interact in a complex manner to detect and eliminatepathogens. Detection and elimination depend upon chem-ical bonding: surfaces of immune system cells are coveredwith various receptors, some of which chemically bind topathogens, while others bind to other immune system cellsor molecules to enable the complex signaling system thatmediates the immune response.7

ImmunomodulatorsThese are biological or synthetic substances that canstimulate, suppress or modulate any aspect of the immunesystem including both adaptive and innate arms of theimmune system.

Classification of immunomodulatorsClinically, immunomodulators can be classified into thefollowing three categories:

Immunoadjuvants are used to enhance the efficacy ofvaccines and therefore could be considered specific immunestimulants. Immunoadjuvants hold the promise of beingthe true modulators of the immune response. It has beenproposed that they be exploited as selectors betweencellular and humoral helper T1 (Th1) and helper T2 cells(Th2), immunoprotective, immunodestructive, and reagenic[immunoglobulin E (IgE)] versus IgG type immune respon-sesdposing a real challenge to vaccine designers.8

Immunostimulants are inherently non-specific as theyare envisaged as enhancements to a body’s resistance toinfection. They can act through innate as well as adaptiveimmune responses. In healthy individuals, the immunosti-mulants are expected to serve as prophylactic and promoteragents, i.e., as immunopotentiators, by enhancing the basiclevel of immune response. In the individual with impairmentof immune response, they are expected to act as immuno-therapeutic agents.9

Immunosuppressants are a structurally and functionallyheterogeneous group of drugs, which are often concomi-tantly administered in combination regimens to treatvarious types of organ transplant rejection and autoimmunediseases.10

Table 1 A brief description of common plant-derived immunomodulators

Botanical (Family) Ayurvedic/Common name

Part used Chemical constituents Other biological activities

Ocimum sanctum Linn. (Labiateae) Tulasi Entire plant Essential oils such as eugenol, cavacrol,derivatives of ursolic acid, apigenin

Carminative, stomachic, antispasmodic,antiasthmatic, hepatoprotective.12e15

Morus alba Linn. (Moraceae) Brahmdaru Fruits, leaves,bark

Flavonoids, anthocyanins Expectorant, hypocholesterolaemic,diuretic.16

Panax ginseng Wall. (Araliaceae) Ninjin Fruits, root Saponins such as ginsenosides,panaxdiol, panaxtriole and oleanolicacid

Adaptogenic properties,antiarrhythmic.14,17

Achillea millefolium C. Koch(Compositae)

Yarrow Leaves Flavonoids, alkaloids, polyacetylenes,coumarins, triterpenes

Anti-inflammatory, antispasmodic,antipyretic, diuretic.18

Aloe vera Tourn.ex Linn. (Liliaceae) Kumaari Gel from leaves Anthraquinone glycosides Purgative, emmenagogue, emollient,antinflammatory.14,19e21

Andrographis paniculata Nees(Acanthaceae)

Kaalmegha Leaves Diterpenes Hepatoprotective, antispasmodic, bloodpurifier, febrifuge.14,22

Asparagus racemosus Wild. (Liliaceae) Shatavaari Roots Saponins, sitosterols Ulcer healing agent, nervine tonic, anti-gout.15,23

Murraya koenigii (L) Spreng. (Rutaceae) Surabhini-nimba Leaves Coumarin, carbazole alkaloids, glucoside Antifungal, insecticidal, insecticidal. 14,24

Couroupita guianensis Aubl.(Lecythidaceae)

Nagalinga Fruits, flowers Steroids, flavonoids, phenolics Antifungal.25

Tinospora cordifolia Miers.(Menispermiaceae)

Amrita, guduuchii Entire herb Alkaloidal constituents such asberberine, tinosporic acid

Hypoglycaemic agent, antipyretic.15,26

Lagenaria siceraria Mol. (Cucurbitaceae) Katu-tumbi Leaves, fruit Cucurbitacin, beta-glycosidase Purgative, emetic.27

Terminalia arjuna Roxb. (Combretaceae ) Arjuna Leaves, bark Flavonoids, oligomericproanthocyanidins, tannins

Cardiotonic, diuretic, prescribed forhypertension.28

Bauhinia variegata Linn.(Caesalpiniaceae)

Kaanchana Roots, bark, buds Flavonoids, beta-sitosterol, lupeol Antifungal, astringent.29

Urena lobata Linn. (Malvaceae) Naagabala Roots, flowers Flavanoids Diuretic, emollient, antispasmodic.30

Gymnema sylvestre R.Br.(Asclepiadaceae)

Gurmaar Leaves Sapogenins Antidiabetic, diuretic, antibilious.31

Cordia superba Cham. and C. rufescensA. DC. (Boraginaceae)

Shleshmaataka Leaf, fruit, bark Alpha-amyrin Anti-inflammatory, antimicrobial.32

Picrorhiza scrophulariiflora Benth.(Scrophulariaceae)

Kutki Roots Iridoid glycosides, amphicoside Antioxidant.33

Heracleum persicum Desf. (Apiaceae) Golpar Shurb Flavonoids, furanocoumarins Antimicrobial.34

Cissampelos pareira Linn.(Menispermiaceae)

Paatha Roots Hayatine alkaloids Antipyretic, analgesic, antilithic.35

Abutilon indicum linn. (Malvaceae) Atibalaa Whole plant Flavonoids, triterpenoids Diuretic, antibacterial.36

Chlorophytum borivilianum Sant. F(Liliaceae)

Safed musli Roots Sapogenins Antifungal.37

Alternanthera tenella Colla(Amaranthaceae)

Snow Ball Herb Flavonoids, triterpenes Antitumor, anti-inflammatory.38

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Table 1 (continued)

Botanical (Family)Ayurvedic/Common name Part used Chemical constituents Other biological activities

Ganoderma lucidum (Fr.) P. Karst.(Polyporaceae)

Reishi mushroom Whole plant Flavonoids, triterpenes Antioxidant.39

Nyctanthes arbor-tristis L. (Oleaceae) Paarijaata Leaf, seeds Iridoid glucosides Anti-inflammatory, antispasmodic.40

Actinidia macrosperma C. F. Liang(Actinidiaceae)

Actinidia Fruits Alkaloids, saponins Antileprotic.41

Acacia catechu Willd. (Leguminosae) Khadira Leaf Flavonoids, quercetin Hypoglycaemic, astringent.14,15,42

Boswellia spp. (Burseraceae) Shallaki Gum resin Triterpenes, ursanes Hypoglycaemic.43

Hibiscus rosa sinensis Linn. (Malvaceae) Japaa Flowers Cyclopropanoids Antidiarrheal, anti-inflammatory.44

Cleome gynandra Linn. (Capperdiceae) Tilaparni Leaf, seeds, rots Hexacosanol, kaempferol Anti-inflammatory.44

Hyptis suaveolens (L.) Poit. (Lamaceae) Tumbaaka Leaf, flowers Lupeol, beta-sitosterol Carminative, antispasmodic.45

Randia dumetorum Lamk. (Rubiaceae) Madana Fruits Saponins, triterpenes Chlorosis, antiarthritic.46

Allium hirtifolium Boiss. (Alliaceae) Persian shallot Herb Thiosulfinates, flavonoids Antirheumatic, anti-inflammatory.47

Citrus natsudaidai Hayata (Rutaceae) Japanese summergrape fruit

Fruits Auraptene, flavonoids Antioxidant.48

Acanthopanax sessiliflorus (Rupr. &Maxim.) (Araliaceae)

Prickly spine Shoots and roots Biopolymers Lympho-proliferative activity.49

Agelas mauritianus (Porifera) Agelas Sponge Glycolipid (a-galactosylceramide) Phagocytotic activity.50

Aphanothece halophytica (Chroococcales) Cyanobacterium Exopolysaccharide Inhibits influenza virus.51

Apium graveolens Linn. (Apiaceae) Celery Seeds Leaves, seeds Flavonoids, coumarins Anti-inflammatory.52

Genus Ardisia (Myrsinaceae) Marlberry Shrub, Branchesand leaves

Peptides, saponins, Isocoumarins,quinones and alkyl phenols

Antimetastatic drug, anti-HIV property.53

Genus Aristolochia (Aristolochiaceae) Pipevine Leaves Aristolochic acid Antiangiogenic, employed in prostatecancer.54

Artemisia annua Linn. (Compositea) Wormwood Herb Artemisinin Immunosuppressive.55

Genus Aspergillus (Trichocomaceae) Aspergillus Fungus Polyene, triazole Antifungals.56

Botryllus schlosseri (Botryllidae) Botryllus Tunicates Cytokines Antioxidant, antiviral, antimicrobial andantitumoral.57

Bidens pilosa L. (Asteraceae) Beggar-ticks Flowers, leaves Polyacetylenes Anti-inflammatory, immunosuppressive,antibacterial and antimalarial.58

Boerhaavia diffusa (Nyctaginaceae) Punarnava Herb Alkaloid Immunostimulatory.59

Bugula neritina L. (Bugulidae) Brown bryozoans Marineinvertebrates

Macrocyclic lactones Immunomodulator.60

Byrsonima crassa Nied. (Malpighiaceae) Byrsonima Leaves Flavonoids, tannins, terpenes Antimicrobial, antioxidant.61

Calendula Officinalis L. (Asteraceae) Garden Marigold Flowers Polysaccharides, proteins, fatty acids,carotenoids, flavonoids, triterpenoids

Antitumor antiviral activity, anti-HIVproperties.62

Camellia sinensis L. (Theaceae) Tea Leaves (�)Epigallocatechin gallate, quercetin,gallicacid

Anticancer activity, lipid lowering activity,anticataract activity, hepatoprotective andantioxidant.63

Cannabis sativa (Cannabaceae) Common hemp Leaves Cannabinoids Immunomodulatory.64

Carpobrotus edulis L. (Aizoaceae) Fig Marigold Flowers, fruit Alkaloids Immunomodulator.65

Centella asiatica Linn. (Umbelliferae), Brahmi Herb Triterpenoid saponins Immunomodulator.66

168D.Kumaretal.

Cistanche deserticola (Orobanchaceae) Cistanche Herb Polysaccharide Immunomodulator, mitogenic andcomitogenic activities.67

Cliona celata (Clionaidae) Borimg sponge Sponge Clionamide, dehydrodopamine Antibacterial activity.68

Cordyceps militaris L. (Clavicipitaceae) Militaris Fungus Cordycepin, cordyceps acid Anti-inflammatory.69

Crinum latifolium Andr. (Amaryllidaceae) Milk and Wine Lily Herb Alkaloids Immunomodulator.70

Dracocephalum Kotschyi (Lamiaceae) Dragon-Head Herb Essential oil Immunomodulator.71

Echinacea angustifolia (Asteraceae) Cone flower Flowers Polysaccharide Treatment for common cold,immunomodulator.72

Eclipta alba L. (Compositae) Bringraja Leaves Triterpenoid glucoside Anticancer, antileprotic, analgesic,antioxidant, antimyotoxic.73

Euphorbia hirta linn. (Euphorbiaceae) Asthma weed Herb Quercitol, myricitrin, gallic acid Anti-inflammatory activity, sedative andanxiolytic activity.74

Evolvulus alsinoides Linn.(Convolvulaceae)

Shankhpushpi Herb Alkaloids Brain tonic.75

Haussknechtia elymatica (Apioideae) Haussknechtia Herb Phenolics Immunomodulator.76

Inonotus obliquus Pers.(Hymenochaetaceae)

Chaga Mushroom Mushroom Polysaccharide Antitumor.77

Larrea divaricata DC. (Zygophyllaceae) Creosote Bush Herb Lignans Anti-inflammatory.78

Lycium barbarum Linn. (Solanaceae) Fruits Polysaccharide-protein complex Antioxidant.79

Matricaria chamomilla (Rhabdoviridae) Chamomile Flowers Protein Immunomodulator.80

Mollugo verticillata L. (Molluginaceae) Carpetweed Herb Quercetin, triterpenoid glycosid Immunomodulator.81

Moringa oleifera L. (Moringaceae) Sahijan Leaves Vitamin A, B, C, carotenoids, sa Antioxidant.82

Pestalotiopsis leucothes(Amphisphaeriaceae)

Fungus Terpenes Immunomodulator.83

Piper longum L. (Piperaceae) Pipali Fruits Alkaloids Antioxidant.84

Rhodiola imbricate Gray. (Crassulaceae) Roseroot Rhizomes Phenolics Immunostimulating properties.85

Silybum marianum L. (Asteraceae) Milk Thistle Flowers Flavonoid Antioxidant.86

Salicornia herbacea (Chenopodiaceae) Glasswort Herb Polysaccharides Immunomodulator.87

Viscum album L. (Loranthaceae) Mistletoe Leaves and youngtwigs, berries

Viscotoxins, polyphenols,polysaccharides

Antitumoral effect.88

Thuja occidentalis L. (Arborvitae) White cedar Leaves Polysaccharides Immunomodulator.89

(�) Z levo form.

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es

esponins

Figure 2. Bioactive molecules showing immunomodulatory activity.

170 D. Kumar et al.

Correlation of immunomodulators with AyurvedaAyurveda is a most ancient and yet currently vital traditionpracticed widely in India, Sri Lanka and other countries. Ithas a sound philosophical and experimental basis. Athar-vaveda (around 1200 BC), Charak Samhita and SushrutSamhita (1000e500 BC) are the main classic referencecollections that give a detailed description of over 700herbs.

Concept of Rasayana

The word Rasayana, a combination of two words (rasa andayana), refers to nutrition and its transportation throughoutthe body. Rasayana therapy enhances the qualities of rasa,enriching it with nutrients so one can attain longevity,improved memory and intelligence, freedom from disorder,youthfulness, excellence of hair, complexion and voice,optimum development of physique and sense organs,

Figure 3. Esculetin (6, 7- dihydroxycoumarin) show immu-nomodulatory activity.

mastery over phonetics and brilliance. As a dedicatedstream of medication for immune promotion, anti-degenerative and rejuvenating health care, the Rasayanatherapy of Ayurveda is known to prevent the effects ofageing and improve the quality of life for healthy as well asdiseased individuals. Rasayana is helpful to improveimmunity and is normally advised during the degenerativephase of life, which starts from around 45 years in bothmales and females.11

Plants as immunomodulators

Several medicinal plants used in the Indian traditionalsystem known as Rasayana (devoted to enhancement of thebody’s resistance) have attracted the attention of scientistsworld-wide. As discussed below, several medicinal plantsexhibit not only immunomodulatory activity but also a widerange of antioxidant, antiasthmatic, antiarrhythmic, anti-inflammatory, hepatoprotective, hypocholesterolemic,antifungal, cardiotonic, diuretic, and other medicinalactivities (Table 1).12e89

Chemistry of plant-derived immunomodulators

GlycosidesThese organic compounds from plant and animal sources,upon enzymatic or acid hydrolysis, yield one or more sugarmoieties. Chemically, they are the acetals or sugar ethers,formed by the interaction of the hydroxyl groups of thesugar and non-sugar moieties, with the loss of a water

Figure 4. Compound 1-10 show cytotoxic action and potential immunomodulation effect.

Immunomodulators in traditional Indian health care 171

molecule. Numerous glycosides have been shown to exertthe desired immunomodulatory action and their structuresare shown in Fig. 2 (relevant numbers in parentheses).Examples include iridoid glycosides (1) Picrorhiza scrophu-lariiflora and anthraquinone glycosides (2) Andrographispaniculata. Dendroside A and dendronobilosides A and B,three new sesquiterpene glycosides, have been isolatedfrom the stems of Dendrobium nobile, a plant used inChinese traditional medicine. Dendroside A and den-dronobilosides A and B were found to stimulate the prolif-eration of murine T and B lymphocytes in vitro, while

Figure 5. Plant alkaloids with

dendronobiloside B showed inhibitory activity in this sameassay.

FlavonoidsChemically, flavonoids have a fifteen carbon skeleton (C6-C3-C6) which consists of two phenyl rings connected bya three-carbon bridge. Several types of flavonoids exertimmunomodulatory activities, including apigenin (3), olig-omeric proanthocyanidins (4), isoflavonoids, flavones, andanthocyanidins. Such flavonoids are found in Terminaliaarjuna.

immunomodulatory activity.

Figure 6. Flavonoids showing immunomodulatory activity.

Figure 8. Active ginsenosides.

Figure 7. Ganoderic acids.

172 D. Kumar et al.

Figure 9. Celastrol, bryonolic acid and glycyrrhetinic acid.

Immunomodulators in traditional Indian health care 173

CoumarinsThese glycosides are derivatives of benzo-a-pyrone (5); thefuranocoumarins (6) are formed by fusion of furan ring toa coumarin at either the 6 and 7 position or the 7 and 8position90. These glycosides also exert immunomodulatory

Figure 10. Active

activities. Examples include Achillea millefolium, Herac-leum persicum and auraptene (7) from Citrus natsudaidaimentioned above. Esculetin (6,7-dihydroxycoumarin) isa coumarin derivative that can be isolated from manyplants such as Artemisia capillaries, Citrus limonia and

cucurbitacins.

Figure 11. Nor-friedolanes from Tripterygium wilfordii.

174 D. Kumar et al.

Euphorbia lathyris. It is known to exhibit pleiotropic bio-logical activities including lipoxygenase-inhibitory activity,free radical scavenging activity, suppressive activity onoxidative damage to DNA, tyrosinase-inhibitory activity aswell as being cancer chemopreventive and having anti-tumor activities (Fig. 3) .91 Cytotoxic coumarins are derivedfrom the root of Angelica dahurica (Fig. 4).92

SapogeninsSapogenins, such as triterpenoid saponins (8) and diter-penes (9) exert a wide range of immunomodulatory

Figure 12. Oleananes from

activities. Examples are Gymnema sylvestre, Chlorophytumborivilianum, Boswellia spp. and Randia dumetorum.

AlkaloidsThese organic compounds are of natural or synthetic origin,basic in nature, containing one or more nitrogen atoms,normally heterocyclic, of limited distribution and havespecific physiological actions on the human or animalbody.90 Achillea millefolium, Murraya koenigii, Cissampe-los pareira and Actinidia macrosperma are the examples ofalkaloids discussed in this review.

Tripterygium wilfordii.

Figure 13. Boswellic acids.

Figure 14. Saponins from Pueraria Lobata and Actaea Podocarpa.

Immunomodulators in traditional Indian health care 175

Figure 15. Avicin G and Buddle j asaponin IV.

176 D. Kumar et al.

ThiosulfinatesThese compounds (10) also demonstrate potent immuno-modulatory and adaptogenic properties, e.g., from Alliumhirtifolium.47

Volatile oils and terpenoidsThe term terpene represents the hydrocarbons (C5H8),while terpenoids include the hydrocarbon as well as their

Figure 16. Active principles from Acanthopanax koreanum, Liqanolic acid.

oxygenated derivatives. Terpenes like carvacrol (11) andthe terpenoids are all volatile oils of plant or animalorigin.90 Various plant constituents with terpene moietyexhibit immunomodulatory activity, e.g., eugenol (12) fromOcimum sanctum, diterpene from Andrographis paniculata,Achillea millefolium, Alternanthera tenella, triterpenes(13) from Ganoderma lucidum, lupeol (14) and amyrine (15)in in Bauhinia variegate.

uidombar formosana and semisynthetic derivatives from ole-

Table 2 Pharmacology of immunomodulatory activities from putative medicinal plants

Plant/Family name Dose administered Type of solventextract

In vitro/in vivo model Mechanism involved and observation

Ocimum sanctum Linn.(Labiateae)

200 mg/kg p.o. Aqueous/alcoholic HA titer Extract shows increased DTH to sheep red blood cells SRBCs.Alcoholic extract was more potent than aqueous in producingdelayed type hypersensitivity response. Both extracts havemarginal stimulatory effect on humoral immunity.12

3 mg/kg, i.p. Seed oil HA titer Oil shows significant immunomodulatory effect, increase inSRBCs antibody titer and a decrease in percentage histaminerelease from the peritoneal mast cell of sensitized rats(humoral immune responses); also a decrease in footpadthickness and percentage leucocyte migration inhibition (cell-mediated immune responses) is observed.13

Morus alba Linn. (Moraceae) 100 mg/kg,1 g/kg,p.o.

Methanolic HA titer, carbon clearanceassay, cyclophosphamideinduced neutropenia andneutrophil adhesion test

Extract affects humoral immunity as shown in the indirecthemagglutination test, serum immunoglobulin levels and micelethality test. It also affects cell-mediated immunity, showingsignificant increase in the neutrophil adhesion, carbonclearance and a reduction in cyclophosphamide inducedneutropenia.16

Panax ginseng Wall.(Araliaceae)

100 mg, p.o. Liquid ginsengextract

Double-blind, placebo-controlled eight-week study

Blood samples collected at baseline and week four. At weekeight examined PMN cell chemotaxis, phagocytosis, totallymphocytes, T-helper and T-suppressor cells, and NK-cellactivity. Groups receiving ginseng experienced consistentimprovement in immune system activity at week four andstatistically significant differences at week eight, evidenced byimprovements in PMN cell chemotaxis, phagocytosis, and totalnumber of T-helper and T-suppressor cells.17

Achillea millefolium C. Koch(Compositae)

100 mg/kg, i.p. Alcoholic DTH, HA titer Extract exhibits significant stimulatory effect on both humoraland cellular immune functions in mice. Aqueous extract ofplant shows significant increase in the delayed type ofhypersensitivity response at a dose of 100 mg/kg. In thehemagglutination test, plant extract shows stimulatory effectin all doses.34

Aloe vera Tourn.ex Linn.(Liliaceae)

100 g/mL Hydrogel Mouse macrophage cell line,RAW 264.7

Acemannan (primary polysaccharide from Aloe vera gel)incubated on special type of mouse macrophage cell line, RAW264.7 for 24 h causes immunostimulation due to activation ofmacrophages.19,20,21

Andrographis paniculata Nees(Acanthaceae)

Dose dependent Alcoholic Mitogen inducedlymphocyte proliferation

Andrographolide acts as inhibitor of TNF-a and inducessignificant stimulation of both “antigen specific” and “antigennonspecific” types of immune responses in mice, showingeffectiveness against a variety of infectious and oncogenic(cancer causing) agents.22

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Table 2 (continued)

Plant/Family name Dose administeredType of solventextract In vitro/in vivo model Mechanism involved and observation

Asparagus racemosus Wild.(Liliaceae)

100 mg/kg bodyweight

Aqueous HA titer Aqueous extract showed immunoadjuvant effect onexperimental animals when immunized with diphtheria,tetanus, and pertussis vaccine. Reduced mortality coupledwith overall improved health status was observed in treatedanimals, indicating the development of a protective immuneresponse.23

Murraya koenigii (L) Spreng.(Rutaceae)

250 and 500 mg/kg,p.o.

Methanolic HA titerDTH, NO assay,phagocytic activity

Extract showed immunostimulation in vitro and in vivo.Significant increase in NO production by mouse peritonealmacrophages is detected in cultures. Supernatants indicatedincrease phagocytic activity of macrophages thus increase inphagocytic index by rapid removal of carbon particles fromblood stream.24

Couroupita guianensis Aubl.(Lecythidaceae)

100e200 mg/kg,p.o.

Aqueous,methanolic

In vitro phagocytic activity,HA titer, hypersensitivityresponse

Extract showed immunostimulation in vitro and in vivo andincreased phagocytic activity thus an increase in phagocyticindex and in DTH.25

Tinospora cordifolia Miers.(Menispermiaceae)

p.o. Aqueous,methanolic

In vitro phagocytic activity,HA titer, hypersensitivityresponse, inhibition ofallogenic transplantrejection

Improves the phagocyte function without affecting cell-mediated and humoral immune systems and also causesinhibition of C3 canvertase of the classical complementpathway, hence acts as immunomodulator.26

Lagenaria siceraria Mol.(Cucurbitaceae)

23 mg/kg ,i.p. Ethanolic HA titer, DTH Extract showed immunostimulation in vitro and in vivo byincreasing the DTH.27

Terminalia arjuna Roxb.(Combretaceae)

400 mg/kg, p.o. Aqueous, alcoholic HA titer Plant showed immunomodulation by increasing the secondaryimmune response as evidenced by an increase in Anti- SRBCantibody titre (ASRBs) antibody titer but failed to modulateprimary immune response.28

Bauhinia variegata Linn.(Caesalpiniaceae)

250e500 mg/kg,p.o.

Ethanolic Carbon clearance test andneutrophil adhesion test,HA titer

Increase in macrophage stimulatory activity, neutrophiladhesion and hemagglutination antibody titer confirms itsimmunomodulatory potential.29

Urena lobata Linn. (Malvaceae) 5100 mg/mL Methanolic Phagocytic activity, Extract showed immunostimulation in vitro and increasedphagocytic activity thus increases in phagocytic index.30

Gymnema sylvestre R.Br.(Asclepiadaceae)

25 mg/mL, 50 mg/mLand 100 mg/mL

Aqueous Neutrophil locomotion andchemotaxis test,phagocytosis of killedCandida albicans andnitroblue terazolium tests

Extract showed significant immunomodulation at allconcentrations in various in vitro models by exertinga stimulating effect on phagocytic activity, neutrophillocomotion and chemotaxis.31

Cordia superba Cham. andC. rufescens A. DC.(Boraginaceae)

100 mg/mL Methanolic NO assay,lymphoproliferation assay,cytotoxicity assay, Myxedlymphocyte reaction

Extract showed a significant immunomodulation by stimulatingthe NO, IFN-g and lipopolysaccharide.32

178D.Kumaretal.

Picrorhiza scrophulariifloraBenth. (Scrophulariaceae)

Differentconcentrations

Diethyl ether, ethylacetate, aqueous,methanolic

Chemiluminescence and T-cell proliferation assay, DTH

Strong inhibitory activity of P. scrophulariiflora towards theclassical pathway of complement, chemiluminescence and T-cell proliferation assay was observed for the diethyl etherextract.33

Heracleum persicum Desf.(Apiaceae)

50, 100 and 200 mg/kg

Aqueous DTH, HA titer Stimulates both humoral and cellular immune system, alsostimulates the production of interleukin-6. Aqueous extract ofplant shows significant increase in DTH at doses of 50, 100 and200 mg/kg. In hemagglutination test, plant extract showedstimulatory effect in all doses.34

Cissampelos pareira Linn.(Menispermiaceae)

75 mg/kg, p.o. Aqueous, ethanolic HA titer, DTH Stimulates immune system, affects humoral immunity as shownby its effect in the indirect hemagglutination test, serumimmunoglobulin levels. It also affects cell-mediatedimmunity.35

Abutilon indicum linn.(Malvaceae)

200, 400 mg/kg Aqueous, ethanolic HA titer, DTH, neutrophiladhesion test and carbonclearance test

Stimulates immune system, affects humoral immunity as shownby its effect in the indirect hemagglutination test, serumimmunoglobulin levels. Also affects cell-mediated immunity,showing significant increase in neutrophil adhesion and carbonclearance.36

Chlorophytum borivilianumSant. (Liliaceae)

100-200 mg/kg Ethanolic Azathioprine-inducedmyelosuppresion, DTH , %neutrophil adhesion, carbonclearance

Observed an increase in DTH, % neutrophil adhesion and in vivophagocytosis by carbon clearance method after treatment withextracts, proving its potential as an immunomodulator.37

Alternanthera tenella Colla(Amaranthaceae)

50, 100 or 200 mg/kg, i.p.

Aqueous Plaque-forming cell assaysand enzyme-linkedimmunosorbent assay

Immunostimulation through modulation of B-lymphocytefunctions was achieved using aqueous extracts of A. tenella.38

Ganoderma lucidum (Fr.)P. Karst. (Polyporaceae)

12.5, 100, 400 mg/mL

Aqueous, ethanolic,ammonium oxalate,sodium hydroxide

Cytokine assay (TNF-a, IFN-g)

Induction of cytokine (TNF-a, IFN-g) by Ganoderma suggests itsimmunomodulatory potential.39

Nyctanthes arbor-tristisL. (Oleaceae)

50, 100, 150 and200 mg/kg

Ethanolic HA titer, DTH Potentially stimulates immune system and affects bothhumoral immunity as well as cell-mediated immunity as shownby its effect in the indirect hemagglutination test and serumimmunoglobulin levels.40

Actinidia macrosperma(Actinidiaceae)

250 mg/kg Aqueous Lymphocyte proliferationassay, NK cell cytotoxicity

Acts as immunomodulator by lymphocyte proliferationstimulation and by activating NK cells.41

Acacia catechu (Leguminosae) 5 mg/kg and 50 mg/kg, p.o.

Aqueous Neutrophil adhesion test,mice lethality test, carbonclearance assay,cyclophosphamide inducedneutropenia, serumimmunoglobulin levels andthe hamagglutination test

Aqueous extract affects humoral immunity as shown by itseffect in the indirect hemagglutination test, serumimmunoglobulin levels and mice lethality test. It also haseffect on the cell-mediated immunity, showing significantincrease in the neutrophil adhesion, carbon clearance and areduction in cyclophosphamide induced neutropenia.42

Boswellia spp. (Burseraceae) 100 mL/mL Oil Lymphocyte proliferationassay

Stimulatory effect on lymphocyte proliferation.43

(continued on next page)

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Table 2 (continued)

Plant/Family name Dose administeredType of solventextract In vitro/in vivo model Mechanism involved and observation

Hibiscus rosa sinensis Linn.(Malvaceae)

75, 150 and 300 mg/kg, p.o.

Hydro alcoholic Carbon clearance, HA titerand footpad swellingmethod

Stimulatory effect on both humoral immunity as well as cell-mediated immunity by stimulating phagocytosis, increases inDTH.44

Cleome gynandra Linn.(Capperdiceae)

50, 100 and 200 mg/kg, p.o.

Ethanolic Carbon clearance, HA titerand footpad swellingmethod

Stimulatory effect on both humoral immunity as well as cell-mediated immunity by stimulating phagocytosis, increases inDTH.44

Hyptis suaveolens (L.) Poit.,(Lamaceae)

50, 70 mg/kg Alcoholic HA titer and % paw volumedetermination

Potentially suppresses immune system affecting both humoralimmunity and cell-mediated immunity as shown by its effect inindirect hemagglutination test.45

Randia dumetorum Lamk.(Rubiaceae)

100 mg/kg Chlorofom,petroleum ether,methanolic

DTH, cyclophosphamideinduced mylosuppressionmodel

Modulates immune system depending upon fractions andmechanism involved in stimulation and increase in DTHresponse.46

Allium hirtifolium Boiss.(Alliaceae)

100e1000 mg/kg Hydro alcoholic SRBC induced footpadthickness,

Increase in footpad thickness due to immunomodulatoryactivity .47

Citrus natsudaidai Hayata(Rutaceae)

100, 200 or 400 mg/kg, “p.o.”

Oil lymphocyte proliferationassay, cytokineassay

Immunostimulatory effect on lymphocyte proliferation,induction of cytokine (TNF-a, INF-g).48

DTH Z delayed type hypersensitivity response; HA Z hemagglutination; IFN- g Z interferon-g; i.p. Z intraperitoneal injection; NK Z natural killer; NO Z nitric oxide;PMN Z polymorphonuclear; p.o. Z per ossa; SRBC Z sheep red blood cells; TNF-a Z tumor necrosis factor-a.

180D.Kumaretal.

Immunomodulators in traditional Indian health care 181

PolysaccharidesBotanical polysaccharides exhibit a number of beneficialtherapeuticproperties, and it is thought that themechanismsinvolved in these effects are due to the modulation of innateimmunity and, more specifically, macrophage function.Furthermore, botanical and microbial polysaccharides bindto common surface receptors and induce similar immuno-modulatory responses in macrophages, suggesting thatevolutionarily conserved polysaccharide structural featuresare shared between these organisms. Thus, the evaluation ofbotanical polysaccharides provides a unique opportunity todiscover novel therapeutic agents and adjuvants that exhibitbeneficial immunomodulatory properties. The immunomod-ulatory effects of the polysaccharide of Cistanche deserti-cola have been evaluated by in vitro proliferation of murinethymus lymphocytes using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) method. Theenhancing effect of polysaccharide on murine thymuslymphocyte proliferation was related to its delivery ofthymus intracellular calcium ions (Ca2þ). High molecularweight substances were isolated from Salicornia herbacea,which has been used in traditional oriental remedies to treata variety ofdiseases includingcancer. Theactive componentsof the extract havebeendescribed as polysaccharides,whichnot only vigorously activate monocytic cells, but also inducedifferentiation of monocytic cells into macrophages.93, 94

The chemical structure of some immunomodulator agentsare shown in Figs. 2e16.

Pharmacology of immunomodulatory activitiesfrom putative medicinal plants

Mechanism of action of the Rasayanas/immunomodulatorsIt has been reported that the “Rasayanas” are rejuvena-tors, nutritional supplements and possess strong antioxi-dant activities. They also exert antagonistic action onoxidative stressors, giving rise to the formation of differentfree radicals. They are used mainly to combat the effects ofageing, atherosclerosis, cancer, diabetes, rheumatoidarthritis, autoimmune disease and Parkinson’s disease. TheRasayana herbs seem to operate through immunostimulant,immunoadjuvant, and immunosuppressant activities or byaffecting the effector arm of the immune response.11 Mech-anisms of immunomodulation activity occur mainly viaphagocytosis stimulation, macrophages activation, immu-nostimulatory effect on peritoneal macrophages, lymphoidcells stimulation, cellular immune functionenhancementandnonspecific cellular immune system effect, antigen-specificimmunoglobulin production increase, increased nonspecificimmunitymediators and natural killer cell numbers, reducingchemotherapy-induced leukopenia, and increasing circu-lating total white cell counts and interleukin-2 levels(Table 2).12,13,16,17,19e48

Modulation of the immune responses through the stim-ulatory or suppressive activity of a phyto-extract may helpmaintain a disease-free state in normal or unhealthypeople. Agents that activate host defense mechanisms inthe presence of an impaired immune response can providesupportive therapy to conventional chemotherapy.95 A highdegree of cell proliferation renders bone marrow

a sensitive target, especially to various cytotoxic drugs. Infact, bone marrow is the organ most affected during anyimmunosuppression therapy with this class of drugs. Loss ofstem cells and the inability of the bone marrow to regen-erate new blood cells results in thrombocytopenia andleucopenia.96 Saponins are either triterpenoid or steroidalglycosides proven to be essential phytoconstituents withvarious pharmacological activities, such as antiallergic,antiphlogostic, cytotoxic antitumour, antiviral, immuno-modulating, antihepatotoxic, molluscicidal, and antifungalactivity. Recently, three diosgenyl saponins isolated fromParis polyphylla have been reported to have immunosti-mulant properties.97 Lymphocyte stimulation tests wereperformed on eight cycloartane-type saponins isolatedfrom Astragalus melanophrurius,98 to determine the role ofsaponins in the immunomodulating effect of the plant.Higher concentrations of tested compounds have exhibitedinhibitory effects.

Cycloartane and oleanane-type triterpenes from thesespecies have unmistakably induced interleukin-2 activity.99

Immunomodulatory activities of terpenoid compounds suchas glycyrrhizinic acid, ursolic acid, oleanolic acid, andnomilin have been reported.100 A novel triterpenoid hasbeen isolated from the root bark of Ailanthus excelsa Roxb.(Tree of Heaven), AECHL-1, and has potential as an anti-cancer agent.101

Many studies have reported the identification of immu-nomodulatory compounds with pharmacological activityand a limited toxicity. In this context, ethnopharmacologyrepresents the most important way possible to uncoverinteresting and therapeutically helpful molecules. Thephytochemical analysis of Rasayana plants has revealeda large number of compounds including tannic acid, flavo-noids, tocopherol, curcumin, ascorbate, carotenoids,polyphenols, etc., which have been shown to have potentimmunomodulatory properties. The herbal mixture prepa-rations of Indian traditional medicine may stimulateimmunomodulation due to their content of plants withimmunomodulatory properties that probably act synergis-tically. This hypothesis along with the lack of toxicity canbe important to understand their use in the past as well ascurrently.102

From the above review it should be evident that thereare many medicinal plants which exert immunomodulatoryactivity in experimental models at a particular dose.Different types of screening methods both in vivo andin vitro have been employed to determine their pharma-cological activity. Some medicinal plants may stimulate theimmune system, (e.g., Panax ginseng, Ocimum sanctum,Tinospora cordifolia, and Terminalia arjuna), and somemay suppress the immune response (Alternanthera ten-ella). Also, various secondary metabolites (e.g., alkaloids,glycosides, saponins, flavonoids, coumarins, and sterols)exhibit a wide range of immunomodulating activity. Thusa successful review has been achieved by our above survey.

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