Immunomodulatory leads from medicinal plants

Indian Journal of Traditional Knowledge Vol. 13 (2), April 2014, pp. 235-256

Immunomodulatory leads from medicinal plants Pulok K Mukherjee1,*, Neelesh K Nema1, Santanu Bhadra1, D Mukherjee1, Fernão C Braga2 & Motlalepula G Matsabisa3 1

School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata - 700 032, India; 2 Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Olegário Maciel, 2360, Belo Horizonte, Brazil; 3 South African Medical Research Council, Francie van Zijl Drive, Parow Valley, Cape Town, South Africa E-mail: [email protected] Received 19.03.13, revised 23.08.13 Immunomodulation is the alteration of immune response which may increase or decrease the immune responsiveness. Medicinal plants, since times immemorial, have been used virtually in all cultures as a source of medicine for altering the immune systems. Several medicinal plants have been investigated for immunomodulatory potentials and they are proved to have beneficial effect on alteration of immune system by diverse mechanisms in animals. The present review will provide an up to date knowledge about the medicinal plants used as immunomodulators and their phytoconstituents. This article highlights on the phytochemistry, pharmacology, therapeutic usage and related aspects of 55 medicinal plants, such as Allium sativum, Aloe vera, Andrographis paniculata, Azadirachta indica, Boerhaavia diffusa, Boswellia serrata, Curcuma longa, Centella asiatica, Carica papaya, Datura quercifolia, Emblica officinalis, Hydrastis Canadensis, Hypericum perforatum, Ocimum sanctum, Panax ginseng, Plantago major, Plantago asiatica, Piper longum, Tinospora cordifolia, Mangifera indica, Momordica charantia, Withania somnifera, etc. which have been investigated for their immunomodulatory potentials, and they are proved to acquire beneficial effect on alteration of immune system by diverse mechanisms. Thus an approach for integration of the available information on several species of medicinal plants used as immunomodulators along with the metabolites responsible for the same has been made in this article. Keywords: Immunomodulation, Medicinal plants, Natural immunomodulators IPC Int. Cl.8: A61K 36/00, A01C 1/08, A61K 39/00

The term "immunomodulation" means the alteration of immune response which may increase or decrease the immune responsiveness. Enhancement in the immune responsiveness is called immunostimulation and reduction in the immune responsiveness is called immunosuppression. An immunomodulators may be defined as a substance, biological of synthetic, which can stimulate, suppress or modulate any of the components of the immune system including both innate and adaptive arms of the immune response. The essence of immunomodulation is that a pharmacological agent acting under various dose and time regimens displays an immunomodulating effect1,2. Possible mechanism of immunomodulation has been summarized in Fig. 1. The extreme manifestations of immunomodulating action of biologically active substances are immunosuppression and immunostimulation, hence both immunostimulating agents and immunosuppressing agents have their own standing and search for better agents exerting these activities is ______________ *Corresponding author

becoming the field of major interest all over the world3. Natural adjuvants, synthetic agents, antibody reagents are used as immunosuppressive and immunostimulative agents. But there are major limitation to the general use of these agents such as increased risk of infection and generalized effect throughout the immune system4. To overcome these problems a number of drugs from natural source either herbal or mineral have been used as to alter the human immune system5. There are several medicinal plants are employed in different system of medicine throughout the world to improve the immunological disorders. In India use of plants as remedy can be traced back to 6000 BC. Ayurveda – ancient science of life is believed to be prevalent for last 5000 yrs in India6, 7. In recent times modulation of immune response to cure various diseases has been a very interesting concept and the concept of rasayana in ayurveda deals with the same. Ayurvedic system of medicine describes this concept of rasayana under which plants with rejuvenating activity have been described by the emphasis on promotion of health by strengthening host defenses against different diseases. They have been categorized by ayurveda as ‘Rasayan’

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literally meaning a house or place of ‘Ras’, i.e. essential vehicle of life. These plants have been found to have role in the promotion of health by strengthening host defences against different diseases. Beside that these rasayana plants also have other properties like delaying the onset of senescence and improving mental functions by strengthening the psycho-neuro-immune axis8. Therefore a number of plants with their extracts, active fractions have been investigated for immune response modifying activity (Table 1). In addition, biologically active compounds from natural sources have always been of great interest to scientists working on infectious diseases9 or to improve immune function. Hence, in this review attempt has been made to highlight the experimental work on immunomodulation of various Indian medicinal plants along with their possible mechanism of action with possible constituenrts. Medicinal plants and their constituents with immunomodulatory potentials Structures of some important phytoconstituents have given separately in the text from serial No. 1-32 Acorus calamus L. (Araceae)

Acorus calamus commonly known as “Bach or Vacha or Sweet Flag” is a semi-aquatic herb with creeping rhizomes and sword shaped long leaves found throughout India near marshy places, river banks and lakes. The plant showed diverse pharmacological potentials including antibacterial, sedative, spasmolytic, hypocholesterolaemic, insecticide, antiulcer, etc.10. Ethanolic extract of rhizome of the plant proved to possesses anti-cellular and immunomodulatory properties. This extract inhibited proliferation of mitogen and antigen stimulated human peripheral blood mononuclear cells (PBMCs). Further rhizome extract also inhibited growth of several cell lines of mouse and human origin, production of nitric oxide, interleukin-2 (IL-2) and tumor necrosis factor-a (TNF-α)11. Aloe vera (L.) Burm.f. (Asphodelaceae)

Aloe vera is a very well known medicinal plant, grows in arid climates and widely distributed in Africa and other arid areas. It is claimed that Aloe vera has wound and burn healing properties and also posses a strong anti-inflammatory and immunomodulatory effects. The effects of Aloe vera on microcirculation and levels of TNF-α and IL-6 were investigated in rats after inducing burn. It was found that the amount of leukocyte adhesion was significantly reduced in the Aloe vera treated burn-

Fig. 1Mechanism of immunomodulation

wound rats compared to rats in the control group. It was also observed that the levels of TNF-α and IL-6 reduce significantly12. Dihydrocoumarin derivatives (1, 2) were isolated from Aloe vera which exhibited immunomodulatory activity in relation to increasing the phagocytic activity and stimulating the production of superoxide anions in the oxygen respiratory burst of rat peritoneal macrophages13. Allium sativum L. (Alliaceae)

Allium sativum (Garlic) is an essential dietary component cultivated throughout India, and familiar worldwide as garlic. There is some evidence for immunomodulatory effect of garlic or selected garlic constituents showing increased T-lymphocyte blastogenesis and phagocytosis, as well as modulation of cytokine production in vitro and in vivo. Kyo et al. (2001) have found that aged garlic extract showed variety of anti allergic and antitumor through tumor cell growth inhibition and chemopreventative effects14. They demonstated that histamine release in the rat basophil cell line RBL-2H3 was induced by mouse anti-trinitrophenyl (TNP) monoclonal antibody and the TNP-bovine serum albumin (BSA) hapten carrier complex. The extract at doses of 1.25, 2.5 and 5.0 gm/100 gm significantly inhibited the antigen specific histamine release by 50, 80 and 90%, respectively. Oral administration of extract (10 ml/kg) also decreased 25–45% of the ear swelling, used as an index of immunoglobulin IgE mediated skin reaction. In the psychological stress model, the extract significantly prevented the decrease in spleen weight and restored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress20. It is also reported that at low concentration garlic extract

MUKHERJEE et al.: MEDICINAL PLANTS AS IMMUNOMODULATOR

237

Table 1Medicinal plants possessing immunomodulatory properties(Cond.) Sl No. Plant name

Parts used

Immunomodulatory mechanism

1.

Eclipta prostrata (L.) L. (Asteraceae)

Whole plant

41

2.

Phyllanthus emblica L. (Euphorbiaceae)

Fruits

Induces phagocytic index, antibody titer of mice Increase non-specific immune response and lysosomal activity of the humoral responses Imunosuppressive effects on lymphocyte proliferation Restoration of IL-2 and IFN- γ production

3.

Evolvulus alsinoides (L.) L. (Convolvulaceae) Ficus benghalensis L. (Moraceae)

Whole plant

Decreases the level of nitric oxide synthase (NOS) Exert adaptogenic properties Enhance the phagocytosis of the human neutrophils in vitro Increase the antibody titer value

44

5.

Glycyrrhiza glabra L. (Leguminosae)

Bark & root

6.

Hippophae rhamnoides L . (Elaeagnaceae)

Leaves & fruits

7.

Hydrastis canadensis L. (Ranunculaceae) Hypericum perforatum L. (Hypericaceae)

Root

Jatropha curcas L. (Euphorbiaceae) Mangifera indica L. (Anacardiaceae) Matricaria chamomilla L. (Asteraceae) Mollugo verticillata L. (Molluginaceae) Momordica charantia L. (Cucurbitaceae) Morinda citrifolia L. (Rubiaceae) Nelumbo nucifera Gaertn.(Nymphaeceae)

Leaves

Nerium oleander L. (Apocynaceae) Nigella sativa L. (Ranunculaceae)

Leaves

18.

Ocimum tenuiflorum L. (Labiatae)

Aerial parts

19.

Plantago species (Plantago major L. Seed & P. asiatica L. (Plantaginaceae)

20.

Piper longum L. (Piperaceae)

4.

8.

9. 10. 11. 12. 13. 14. 15.

16. 17.

Whole plant

Aerial parts

Fruits Flowers Leaves Fruits & seeds Fruits Rhizome & seed

Seeds

Fruits & leaves

References

43

45

Enhanced immune and antioxidant enzyme activities Stimulates immune cells by CD69 expression on CD4 and CD8 T cells and macrophages function Inhibits chromium-induced free radical production, apoptosis, DNA fragmentation Stimulates IL-2 and IFN-γ production Reduces plasma TNF-α, IFN- γ and NO levels Inhibits the T helper -type 2 cytokine profile Increase candidacidal activity of neutrophils and decreased adhesion function of epithelial cells Alter the function of NF-kB Increase the antibody titers, lymphocyte and macrophage cells Increase in humoral antibody (HA) titre and DTH Enhance production of IgG1 and IgG2b Activation of immune cells of peripheral blood, and increased sensitivity of effector cells to helper signals Inhibits the production of NO

46, 47

Inhibits the release of TNF-α, NO and proliferation of spleen cells induced by PHA and Con A Stimulating the release TNF-α, IL-β, IL-10, IL-12, IFN-γ Reduce NO production, protects mast cells degranulation Express CD40, CD80, CD86 Inhibited haemaglutination antibodies, DTH reaction, phagocytic index etc in mice Reduces pancreatic ductal adenocarcinoma cell (PDA) synthesis of monocyte chemoattractant protein-1 (MCP-1), TNF- α , IL-1β and cyclooxigenase (COX) -2 Inhibits the polymorpho nuclear leukocytes functions Inhibits antigen induced histamine release from the peritoneal mast cells, foot pad thickness and leucocyte migration It expressed higher levels of MHC class II molecules and costimulatory molecules such as CD80 and CD86 It acts on human peripheral blood mononuclear cells (PBMC) through lymphocyte transformation; enhance the secretion of IFN-γ. Increase the total WBC count, bone marrow cellularity, α- esterase positive cells, enhance the total antibody production

55

48

49 50

51 52 53 54

56 59,60

61 62

63

64

65

(Table 1-Contd.)


238

Table 1Medicinal plants possessing immunomodulatory properties Sl No. Plant name

Parts used

21.

Acorus calamus L. (Araceae)

Rhizome

22.

Aloe vera (L.) Burm.f. (Asphodelaceae) Allium sativum L. (Alliaceae) Andrographis paniculata Wall. ex Nees (Acanthaceae) Azadirachta indica A. Juss. (Meliaceae) Asparagus racemosus Willd (Liliaceae) Argyreia speciosa (L. f.) Sweet (Convolvulaceae) Baliospermum montanum (Willd.) Müll.Arg. (Euphorbiaceae)

23. 24. 25. 26. 27. 28.

29.

Bidens pilosa L. (Asteraceae)

30.

Boerhaavia diffusa L. (Nyctaginaceae) Boswellia serrata Roxb. ex Colebr. (Burseraceae) Calendula officinalis L. (Asteraceae) Camellia sinensis (L.) Kuntze (Theaaceae) Capparis zeylanica L (Capparidaceae) Carica papaya L. (Caricaceae)

31. 32. 33. 34. 35.

Increase the production of IL-2, tumor necrosis factor (TNF)-α Leaves Increases phagocytosis and stimulating the production of superoxide Fruits Suppress leukocyte inflammatory cytokine production Aerial parts Increase the production of IL-2, Inhibits of NO production Leaves Increase IgM and IgG production Inhibits of NO synthesis, degranulation of neutrophils Root Increase the production of leucocytosis Enhances the phagocytic activity of the macrophages Root & seeds Enhance the production of circulating antibody titre Increase in DTH reaction Root & leaves Enhances neutrophil phagocytic function such as neutrophil locomotion, chemotaxis Stabilized mast cell degranulation induced by compound 48/80. Whole plant Enhances the cytokine production and white blood cells population Increases IFN-γ promoter activity Root Inhibits human NK cell cytotoxicity in vitro Inhibits production of NO, IL-2 and TNF-α Bark Inhibits passive paw anaphylaxis reaction and mast cells protection Leaves & flowers Inhibits tumor cell proliferation Leaves Leaves Leaves & seeds

36.

Centella asiatica (L.) Urban. (Umbelliferae)

Leaves

37.

Chelidonium majus L. (Papaveraceae) Chrysanthemum indicum L. (Compositae) Cichorium intybus L. (Asteraceae) Citrus aurantiifolia (Christm.) Swingle (Rutaceae) Cryptolepis dubia (Burm.f.) M.R.Almeida. (Apocynaceae) Curcuma longa L. (Zingiberaceae)

Aerial parts

Desmodium gangeticum (L.) DC. (Fabaceae)

Whole plant

38. 39. 40. 41. 42.

43.


Aerial parts Root Fruits & leaves Root Rhizome

References 11 12, 13 14,15 17 18 20 21 22

23

24 26 28

Enhances the neopterin production in peripheral mononuclear cells Prevents myelosupression in mice with cyclophosphamide and potentiats DTH reaction It enhances the phytohemagglutinin responsiveness of lymphocytes It inhibits the classical complement-mediated hemolytic pathway It increases the phagocytic index, total WBC count and Inhibited human peripheral blood mononuclear cell (PBMC) mitogenesis and production of IL-2 and TNF-α Exert antitumor immunostimulatory effect

29

Increases DTH reaction, antibody generation, Potentiates the mononuclear phagocytosis function Increases DTH reaction, phagocytic activity and natural killer (NK) cell activity and IFN-γ secretion Inhibits proliferation of PHA activated mononuclear cells, staphylococcal protein It stimulates the DTH reaction and also increases the humoral antibody production It shows immunomodulation through inhibition of proliferation induced by PMA and anti-CD28 antibody. Also it inhibits the T lymphocytes isolated from healthy donors induced by PHA Enhance NO production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani

34

30 31

32

33

35 36 37 38,39

40

(Table 1-Contd.)


239

Table 1Medicinal plants possessing immunomodulatory properties Sl No. Plant name

Parts used

44.

Acorus calamus L. (Araceae)

Rhizome

45.

Aloe vera (L.) Burm.f. (Asphodelaceae) Allium sativum L. (Alliaceae) Andrographis paniculata Wall. ex Nees (Acanthaceae) Azadirachta indica A. Juss. (Meliaceae) Asparagus racemosus Willd (Liliaceae) Argyreia speciosa (L. f.) Sweet (Convolvulaceae) Baliospermum montanum (Willd.) Müll.Arg. (Euphorbiaceae)

46. 47. 48. 49. 50. 51.

52.

Bidens pilosa L. (Asteraceae)

53.

Boerhaavia diffusa L. (Nyctaginaceae) Boswellia serrata Roxb. ex Colebr. (Burseraceae) Calendula officinalis L. (Asteraceae) Camellia sinensis (L.) Kuntze (Theaaceae) Capparis zeylanica L (Capparidaceae) Carica papaya L. (Caricaceae)

54. 55. 56. 57. 58.

Increase the production of IL-2, tumor necrosis factor (TNF)-α Leaves Increases phagocytosis and stimulating the production of superoxide Fruits Suppress leukocyte inflammatory cytokine production Aerial parts Increase the production of IL-2, Inhibits of NO production Leaves Increase IgM and IgG production Inhibits of NO synthesis, degranulation of neutrophils Root Increase the production of leucocytosis Enhances the phagocytic activity of the macrophages Root & seeds Enhance the production of circulating antibody titre Increase in DTH reaction Root & leaves Enhances neutrophil phagocytic function such as neutrophil locomotion, chemotaxis Stabilized mast cell degranulation induced by compound 48/80. Whole plant Enhances the cytokine production and white blood cells population Increases IFN-γ promoter activity Root Inhibits human NK cell cytotoxicity in vitro Inhibits production of NO, IL-2 and TNF-α Bark Inhibits passive paw anaphylaxis reaction and mast cells protection Leaves & flowers Inhibits tumor cell proliferation Leaves Leaves Leaves & seeds

59.

Centella asiatica (L.) Urban. (Umbelliferae)

Leaves

60.

Chelidonium majus L. (Papaveraceae) Chrysanthemum indicum L. (Compositae) Cichorium intybus L. (Asteraceae) Citrus aurantiifolia (Christm.) Swingle (Rutaceae) Cryptolepis dubia (Burm.f.) M.R.Almeida. (Apocynaceae) Curcuma longa L. (Zingiberaceae)

Aerial parts

Desmodium gangeticum (L.) DC. (Fabaceae)

Whole plant

61. 62. 63. 64. 65.

66.


Aerial parts Root Fruits & leaves Root Rhizome

References 11 12, 13 14,15 17 18 20 21 22

23

24 26 28

Enhances the neopterin production in peripheral mononuclear cells Prevents myelosupression in mice with cyclophosphamide and potentiats DTH reaction It enhances the phytohemagglutinin responsiveness of lymphocytes It inhibits the classical complement-mediated hemolytic pathway It increases the phagocytic index, total WBC count and Inhibited human peripheral blood mononuclear cell (PBMC) mitogenesis and production of IL-2 and TNF-α Exert antitumor immunostimulatory effect

29

Increases DTH reaction, antibody generation, Potentiates the mononuclear phagocytosis function Increases DTH reaction, phagocytic activity and natural killer (NK) cell activity and IFN-γ secretion Inhibits proliferation of PHA activated mononuclear cells, staphylococcal protein It stimulates the DTH reaction and also increases the humoral antibody production It shows immunomodulation through inhibition of proliferation induced by PMA and anti-CD28 antibody. Also it inhibits the T lymphocytes isolated from healthy donors induced by PHA Enhance NO production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani

34

30 31

32

33

35 36 37 38,39

40

(Table 1-Contd.)


240


Parts used


67.

Eclipta prostrata (L.) L. (Asteraceae)

Whole plant

41

68.

Phyllanthus emblica L. (Euphorbiaceae)

Fruits

Induces phagocytic index, antibody titer of mice Increase non-specific immune response and lysosomal activity of the humoral responses Imunosuppressive effects on lymphocyte proliferation Restoration of IL-2 and IFN- γ production

69.

Evolvulus alsinoides (L.) L. (Convolvulaceae) Ficus benghalensis L. (Moraceae)

Whole plant

44

71.

Glycyrrhiza glabra L. (Leguminosae)

Bark & root

72.

Hippophae rhamnoides L . (Elaeagnaceae)

Leaves & fruits

73.

Hydrastis canadensis L. (Ranunculaceae) Hypericum perforatum L. (Hypericaceae)

Root

Jatropha curcas L. (Euphorbiaceae) Mangifera indica L. (Anacardiaceae) Matricaria chamomilla L. (Asteraceae) Mollugo verticillata L. (Molluginaceae) Momordica charantia L. (Cucurbitaceae) Morinda citrifolia L. (Rubiaceae) Nelumbo nucifera Gaertn.(Nymphaeceae)

Leaves

Decreases the level of nitric oxide synthase (NOS) Exert adaptogenic properties Enhance the phagocytosis of the human neutrophils in vitro Increase the antibody titer value Enhanced immune and antioxidant enzyme activities Stimulates immune cells by CD69 expression on CD4 and CD8 T cells and macrophages function Inhibits chromium-induced free radical production, apoptosis, DNA fragmentation Stimulates IL-2 and IFN-γ production Reduces plasma TNF-α, IFN- γ and NO levels Inhibits the T helper -type 2 cytokine profile Increase candidacidal activity of neutrophils and decreased adhesion function of epithelial cells Alter the function of NF-kB Increase the antibody titers, lymphocyte and macrophage cells Increase in humoral antibody (HA) titre and DTH Enhance production of IgG1 and IgG2b Activation of immune cells of peripheral blood, and increased sensitivity of effector cells to helper signals Inhibits the production of NO

Nerium oleander L. (Apocynaceae) Nigella sativa L. (Ranunculaceae)

Leaves

84.

Ocimum tenuiflorum L. (Labiatae)

Aerial parts

85.

Plantago species (Plantago major L. Seed & P. asiatica L. (Plantaginaceae)

86.

Piper longum L. (Piperaceae)

70.

74.

75. 76. 77. 78. 79. 80. 81.

82. 83.

Whole plant

Aerial parts

Fruits Flowers Leaves Fruits & seeds Fruits Rhizome & seed

Seeds

Fruits & leaves

Inhibits the release of TNF-α, NO and proliferation of spleen cells induced by PHA and Con A Stimulating the release TNF-α, IL-β, IL-10, IL-12, IFN-γ Reduce NO production, protects mast cells degranulation Express CD40, CD80, CD86 Inhibited haemaglutination antibodies, DTH reaction, phagocytic index etc in mice Reduces pancreatic ductal adenocarcinoma cell (PDA) synthesis of monocyte chemoattractant protein-1 (MCP-1), TNF- α , IL-1β and cyclooxigenase (COX) -2 Inhibits the polymorpho nuclear leukocytes functions Inhibits antigen induced histamine release from the peritoneal mast cells, foot pad thickness and leucocyte migration It expressed higher levels of MHC class II molecules and costimulatory molecules such as CD80 and CD86 It acts on human peripheral blood mononuclear cells (PBMC) through lymphocyte transformation; enhance the secretion of IFN-γ. Increase the total WBC count, bone marrow cellularity, α- esterase positive cells, enhance the total antibody production

References

43

45

46, 47

48

49 50

51 52 53 54 55 56 59,60

61 62

63

64

65

(Table 1-Contd.)


241


Parts used


87.

Premna tomentosa Willd. (Verbanaceae) Prunella vulgaris L. (Lamiaceae)

Stem bark

66

89.

Psoralea corylifolia L. (Fabaceae)

Leaves

90.

Punica granatum L. (Punicaceae) Rhinacanthus nasutus (L.) Kurz. (Acanthaceae) Salvia officinalis L. (Lamiaceae) Tamarindus indica L. (Leguminosae)

Fruits

Decrease the lymphocyte proliferation and antioxidant levels Stimulates the proliferation of T-lymphocytes and suppressed NO production in lipopolysaccharidestimulated macrophages Up regulates the production of OVA-specific Th1 cytokine (IFN-γ) and down regulated OVA-specific Th2 cytokine Inhibits the leucocyte migration

Whole plant

Increased the production of IL-2 and TNF-α

33

Aerial parts

Induce rat thymocyte proliferation

70

Fruits

Terminalia chebula Retz. (Combretaceae) Tinospora cordifolia (Willd.) Miers (Menispermaceae)

Fruits

Inhibits the phorbol myristate acetate (PMA) stimulated neutrophil function, neutrophil NADPH oxidase activity, and elastase activity Increase in HA titer and DTH reaction

96.

Trigonella foenum-graecum L. (Fabaceae)

Seeds

97.

Urtica dioica L. (Urticaceae) Withania somnifera (L.) Dunal (cultivated var.) (Solanaceae)

Aerial parts

88.

91. 92. 93.

94. 95.

98.

Fruits

Stem & root

Root

Increase the total white blood cell count, bone marrow cellularity and α-esterase positive cells Enhance the macrophage activation Increases the phagocytic index and phagocytic capacity of macrophages, enhancement of thymus and bone marrow cellularities Reduce TNF-α and other inflammatory cytokines by inhibiting the genetic transcription factor Increase total WBC count, bone marrow cellularity, circulating antibody titer, plaque forming cells in the spleen, phagocytic activity of macrophages

References

67

68

69

71,72

73 74

75

76 77

significantly reduced that IL-12 production, but IL-10 production was increased. The TNF-α (tumor necrosis factor), IL-1α, IL-6, IL-8, Tcell interferon-gamma (IFN-γ), IL-2, and TNF-α were observed to decreased significantly with the extract15.

interleukin-2 (IL-2) induction in human peripheral blood lymphocytes23. It was also reported that andrographolide exhibits nitric oxide (NO) inhibitory property in endotoxin-stimulated macrophages17.

Andrographis paniculata (Burm.f.) Wall. ex. Nees. (Acanthaceae)

Azadirachta indica is well known in India and its neighbouring countries for more than 2000 yrs as one of the most versatile medicinal plants having a wide spectrum of biological activity including antiinflammatory, anti-diabetic, antiviral, anticarcinogenic, immunostimultory, etc. Aqueous extract of stem bark has been shown to enhance the immune response of Balb-c mice to sheep red blood cells in-vivo. The aqueous extract showed strong anticomplementary effects with dose, time-dependently, and most pronounced in the classical complement pathway assay. In addition, a dose-dependent decrease in the chemiluminescence of polymorphonuclear leukocytes and a dose-dependent increase in the production of migration inhibition factor by lymphocytes were also

Andrographis paniculata is one of the Chinese and Indian herbs reputed to be effective in the treatment of cold, diarrhea, fever, and inflammation, etc.16. Methanolic extract of A. paniculata has potential for anticancer and immunomodulatory activities in human cancer and immune cells. The extract and its dichloromethane fraction significantly inhibited the proliferation of HT-29 (colon cancer) cells and augment the proliferation human peripheral blood lymphocytes low concentrations. Three diterpene compounds were isolated from the plant, viz. andrographolide (3), 14-deoxyandrographolide and 14-deoxy-11, 12-didehydroandrographolide.These molecules showed enhanced proliferation and

Azadirachta indica A. Juss. (Meliaceae)

242


observed. Neem oil has been shown to possess immunostimulant activity by selectively activating the cell-mediated immune mechanisms to elicit an enhanced response to subsequent mitogenic or antigenic challenge. Neem oil also possesses immunomodulatory effects in mice. The intraperitoneal (i.p.) injection of neem oil in mice showed increased in leukocytic cells after 3 days of treatment. In addition, the peritoneal macrophages of mice exhibited enhanced phagocytic activity and expression of MHC class-II antigens. Nimbidin is a mixture of tetranortriterpenes and is the major active principle of the seed oil of A. indica possessing potent antiinflammatory and antiarthritic activities by inhibiting some of the functions of macrophages and neutrophils relevant to the inflammatory response following both in vivo and in-itro exposure. Oral administration of 5-25 mg/kg nimbidin to rats for 3 consecutive days significantly inhibited the relocation of macrophages to their peritoneal cavities in response to inflammatory stimuli and also inhibited phagocytosis and phorbol-12myristate-13-acetate (PMA) stimulated respiratory burst in these cells. Nimbidin also inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS) stimulated macrophages following in-vitro exposure. Further observation proved that nimbidin also attenuated degranulation in neutrophils assessed in terms of release of β-glucuronidase, myeloperoxidase and lysozyme18, 19. Asparagus racemosus Willd (Liliaceae)

Asparagus racemosus (Shatavari) is recommended in Ayurvedic texts for prevention and treatment of gastric ulcers, dyspepsia and as a galactogogue. The Asparagus genus is considered to be of medicinal importance because of the presence of steroidal saponins and sapogenins in various parts of the plant. A. racemosus is commonly mentioned as a rasayana in the Ayurveda. Immunomodulating property of A. racemosus has been shown to protect the rat and mice against experimental induced abdominal sepsis. Oral administration of decoction of powdered root of A. racemosus has been reported to produce leucocytosis and predominant neutrophilia along with enhanced phagocytic activity of the macrophages and polymorphs. Percentage mortality of A. racemosus treated animals was found to be significantly reduced while survival rate was comparable to that of the group treated with a combination of metronidazole and gentamicin. A. racemosus showed anti-sepsis activity by altering function of macrophages, indicates its possible immunomodulatory property.

Alcoholic extract of A. racemosus has been found to enhance both, humoral and cell mediated immunity of albino mice injected with sheep red blood cells as particulate antigen20. Argyreia speciosa (L. f.) Sweet (Convolvulaceae)

Argyreia speciosa Sweet of the family convolvulaceae, commonly known as Vryddhadaru in Sanskrit, is a woody climber found throughout in India. It has been used as a ‘rasayana’ drug in the traditional Ayurvedic system of medicine. The roots of this plant have been regarded as alternative and tonic, and are said to be useful in rheumatism and diseases of the nervous system. The ethanolic extract of the root of A. speciosa was showed immunomodulatory activity via DTH reaction, effect on humoral immune responses and phagocytic function of the cells. The extract caused increase in DTH reaction and significantly enhanced the production of circulating antibody titre. This indicates the enhanced responsiveness of macrophages and T and B lymphocytes involved in antibody synthesis21. Baliospermum montanum (Willd.) Müll.Arg. (Euphorbiaceae)

Baliospermum montanum of family Euphorbiaceae is a stout under shrub with herbaceous branches from the roots. It is found in tropical and subtropical Himalaya from Kashmir eastwards to Arunachal Pradesh. The immunomodulatory activity of B. montanum has not been reported scientifically. The different concentration (25, 50, 100 µg/ml) of aqueous extract of roots of B. montanum has been shown immunomodulatory activity through neutrophil phagocytic function such as neutrophil locomotion, chemotaxis, immunostimulant activity of phagocytosis of killed Candida albicans and qualitative nitroblue tetrazolium test by using human neutrophils22. Bidens pilosa L. (Asteraceae)

Bidens pilosa is the largest flowering plant family in the world and it is used as an ethnical medicine for bacterial infection or immune modulation in Asia, America and Africa. Aqueous infusion of B. pilosa has an immunolodulatory effect by enhancing the cytokine production and white blood cells population. Hot water extracts from B. pilosa and its butanol fraction increased IFN-γ promoter activity by 2 to 6 folds. From its butanol fraction the responsible molecules, centaurein (4) (EC50 =75µg/ml) and its aglycone (centaureidin) were isolated which showed


augmentation of IFN-γ promoter activity. Centaurein induced the activity of NFAT and NFκB enhancers, located within the IFN-γ promoter23. Boerhaavia diffusa L. (Nyctaginaceae)

It is a common plant grows widely in the tropics in both dry and rainy seasons in India, Nigeria and many other countries. Ethanolic extract of B. diffusa root significantly inhibited the human NK cell cytotoxicity in vitro, IL-2 and TNF-α in human PBMCs the cell proliferation production of NO in mouse macrophage cells. It is also observed that intracytoplasmic IFN-γ and cell surface markers such as CD16, CD25, and HLA-DR did not get affected on treatment with B. diffusa extract24. Solvent fraction of B.diffusa root extract was studied for its effect on cellular and humoral functions in mice. Oral administration of the fraction (25–100 mg/kg) significantly inhibited SRBC-induced delayed hypersensitivity reactions in mice. A significant dose-related increase in antibody titre was observed during pre- and post-immunisation treatment. Eupalitin-3-O-β-D-galactopyranoside (5) isolated from ethanolic extract of B.diffusa which inhibited PHA-stimulated proliferation of peripheral blood mononuclear cells, two-way MLR and NK cell cytotoxicity as well as LPS induced NO production by RAW 264.7. The compound also inhibited production of PHA stimulated IL-2 at the protein and mRNA transcript levels and LPS stimulated TNF-α production in human PBMCs; it also blocked the activation of DNA binding of nuclear factor-KB and AP-1, two major transcription factors centrally involved in expression of the IL-2 and IL-2R gene, which are necessary for T cell activation and proliferation25. Boswellia serrata Roxb. ex Colebr. (Burseraceae)

Boswellia serrata, or Salai, is one of Ayurveda’s most potent anti-inflammatory herbs. On its own or in combination with other herbs, Boswellia is used both externally and internally to treat rheumatoid arthritis, back pain, fibrositis and osteoarthritis. Clinical trials and animal studies with B. serrata have confirmed its antiinflammatory and pain-relieving effects. Boswellic acid (6), is a pentacyclic triterpene acid present in the extract of gum resin of B. serrata. It has been reported that boswellic acid effect on cell mediated and humoral immunity. In concentrations greater than 3.9µg/ml of boswellic acids produced almost similar and dose related inhibition of proliferative responsiveness of splenocytes to

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mitogens and alloantigen. Preincubation of macrophages with different concentrations of boswellic acid enhanced the phagocytic function of adherent macrophages. Sharma et al. (1998) has reported that boswellic acid has antianaphylactic activity and stabilized the mast cell from degranulation against compound 48/80. A significant inhibition in the compound 48/80 induced degranulation of mast cells in dose-dependant manner (20, 40 and 80 mg/kg, p.o.) was observed26. Calendula officinalis L. (Asteraceae)

Calendula officinalis is an important plant in Indian medicinal systems which have diverse medicinal uses including anti-viral, anti-genotoxic, anti-inflammatory properties27. Numbers of immunomodulatory effects have also been attributed to this plant. 70% ethanolic extract of C. officinalis showed mitogenic activity on human peripheral blood lymphocytes and thymocytes. The extract also possesses a proliferative responsiveness activity of human lymphocytes and mixed lymphocyte reaction. The laser activated C. officinalis extract showed a potent in vitro inhibition of tumor cell proliferation on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis28. Camellia sinensis (L.) Kuntze (Theaaceae)

Camellia sinensis (green tea) is being used as a traditional medicine in Vietnam and China for long time for antitumor, antiviral and immunostimulative properties. The extract of C. sinensis enhanced the neopterin production in unstimulated peripheral mononuclear cells, but an effective reduction of neopterin formation in cells stimulated with concanavalin A, phytohemagglutinin, or interferon-γ was found. It was also reported that the extract of C. sinensis in combination with low dose cyclosporine A significantly prolongs graft survival as well as increase the production of immunosuppressive cytokine, IL-10. Further the extract decreases cyclosporine A induced high TGF-β production, which is implicated in cyclosporine A induced nephrotoxicity. It was also reported that the extract inhibited both nonspecific and antigen-specific proliferation of T cells in vitro29. Capparis zeylanica L. (Capparidaceae)

Capparis zeylanica commonly known as Indian caper is a climbing shrub found throughout India and

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it has been used as a 'Rasayana' drug in the traditional Ayurvedic system of medicine. The leaves of the plant are extensively used as counter-irritant, febrifuge, treatment in piles, etc. The immunomodulatory activity of ethanolic and water extracts of C. zeylanica leaves have been repoted by Ghule et al. (2006) through several immunomologica parameters including neutrophil adhesion test, humoral response to sheep red blood cells, delayedtype hypersensitivity reaction, phagocytic activity and cyclophosphamide-induced myelosuppression. The water extract of C. zeylanica leaves at 300 mg/kg, oral dose evoke a significant increase in neutrophil adhesion to nylon fibres. The ethanolic extract dose dependenltly increased antibody titres in mice and potentiated the delayed-type hypersensitivity reaction induced by sheep red blood cells. The ethanolic extract also prevented myelosuppression in mice treated with cyclophosphamide drug30. Carica papaya L. (Caricaceae)

Carica papaya has been traditionally used as ethnomedicine for a number of disorders, including cancer. Various parts including leaves, fruit, seeds, etc. are being used to treat many diseases. Recently C. papaya seed extract is currently being marketed as a nutritional supplement with purported ability to rejuvenate the body condition and to increase energy. The product claims to improve immunity against common infection and body functioning. The crude seed extract and two other bioactive fractions significantly enhanced the phytohemagglutinin responsiveness of lymphocytes and significantly inhibited the classical complement-mediated hemolytic pathway. Otsuki et al. (2010) reported that the aqueous extract of C. papaya leaves exhibits antitumor activity with significant growth inhibition of tumor cell lines. The production of IL-2 and IL-4 was reduced following the addition of C. papaya leaves extract, whereas that of IL-12p40, IL-12p70, IFN-γ and sTNF-α was enhanced without growth inhibition. The cytotoxicity of activated Peripheral blood mononuclear cells (PBMC) against K562 was enhanced by the addition of the extract31.

asiatica extract and its main constituent asiaticoside (7) possesses immunomodulatory activity, acting by increasing phagocytic index and total WBC count. In human peripheral blood mononuclear cells (PBMCs), Centella asiatica (water extract) significantly increases proliferation and the production of IL-2 and TNF-α In contrast, an ethanol extract of Centella asiatica inhibited human PBMC mitogenesis and the production of IL-2 and TNF-α32. Chelidonium majus L. (Papaveraceae)

Chelidonium majus has multiple applications in Korean traditional medicine because of its antitumoral, cytotoxic, anti-inflammatory and antimicrobial activities and has long been known to have anti-inflammatory effects. C. majus has been investigated for immunomodulatory potential and the results proved that methanolic extract of the plant having pronounced immunomodulatory effects. The methanolic extract significantly suppressed the progression of collagen-induced arthritis and inhibited the production of TNF-α, IL-6 IFN-γ, B cells and γδ T cells in spleen and lymph node. The erosion of cartilage was vividly reduced in mouse knees after treatment of the extract. It was also reported by the author that the same extract increased proportion of CD4+, CD25+ regulatory T cells in vivo. Te levels of IgG and IgM rheumatoid arthritis factor were also decreased with the extract33. Chrysanthemum indicum L. (Compositae)

Chrysanthemum indicum has long been used in as a traditional medicine in Korea, China, and Japan to treat various immune-related diseases. Recently, it has been reported that 70% ethanolic extract of C. indicum inhibited skin inflammation in mice by reducing topical edema. Administration of the ethanol extract at 200 mg/kg (i.p.), is leading to substantial reductions in skin thickness and tissue weight, inflammatory cytokine production, neutrophilmediated myeloperoxidase activity, and various histopathological indicators. In addition, the extract was effective at reducing inflammatory damage induced by chronic 12-O-tetradecanoyl-phorbol-13acetate (TPA) exposure34.

Centella asiatica (L.) Urb. (Umbelliferae)

Centella asiatica is commonly known as ‘mandukparni’. It grows mainly in wet areas in India, upto an altitude of 650 m. The plant has several medicinal uses, i.e. sedative, spasmolytic, anti-anxiety and anti-stress action. It is also reported that C.

Cichorium intybus L. (Asteraceae)

Cichorium intybus has an extensive uses in folk medicines in India for the treatment of liver disorders, gallstones, and inflammation of the urinary tract, fever, vomiting, diarrhea, and enlargement of the spleen. It


has been investigated that 70% ethanol extract of the C. intybus showed a complete inhibitory effect on the proliferation of lymphocytes in the presence of phytohaemaglutinin. Effects of the ethanol extract of C. intybus on the immunotoxicity of ethanol were also investigated in ICR strain mice. The results revealed that the combination of C. intybus extract and ethanol showed significant increases in the circulating leukocytes and the relative weights of liver, spleen and thymus, as compared with those in mice treated with ethanol alone. In addition, the splenic plaque forming cells and hemagglutination titers to sheep red blood cells, and the secondary IgG antibody response to bovine serum albumin were markedly enhanced by the extract plus ethanol treatment compared to the treatment of ethanol alone. The mice which received the combination of C. intybus extract and ethanol, a significant increase in delayed-type hypersensitivity reaction, phagocytic activity, natural killer cell activity and cell proliferation as well as IFN-γ secretion were also observed35. Citrus aurantiifolia (Christm.) Swingle (Rutaceae)

In vitro immunomodulatory effect of concentrated juice of Citrus aurantifolia was investigated by Gharagozloo and Ghaderi (2001) using the parameter of production of specific polyclonal antibodies in rabbits. The immunomodulatory effect of the extract was tested in mitogen activated cultured mononuclear cells. The culture results indicated that proliferation of phytohemagglutinin activated mononuclear cells was significantly inhibited by C. aurantifolia juice dose dependently. At the dose of 500 µg/ml of the extract could inhibit proliferation of staphylococcal protein A activated mononuclear cells36. Cryptolepis dubia (Burm.f.) M.R.Almeida. (Apocynaceae)

The ethanol extract of root of the plant Cryptolepis dubia (Syn: C. buchanani) has been reported to possesses immunomodulatory activity in mice and rats. Oral administration of C. buchanani root extract showed significant stimulation of the delayed type hypersensitivity reaction and humoral antibody production. The oral LD50 was found to be more than 3 gm/kg in both rats and mice37. Curcuma longa L. (Zingiberaceae)

Curcuma longa, a perennial herb widely distributed in India. The rhizome of C. longa has numerous medicinl uses including analgesic, anti-inflammatory, wound healing and immunomodulatory activities. The chief constituent of C. longa is curcumin (8), which

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palyed a major role for immunomodulatory activity. Bone marrow cellularity, alpha-esterase positive cells and macrophage phagocytic activity were enhanced by Curcumin administration. Numerous evidences suggest that curcumin can modulate both the proliferation and the activation of T cells. It was reported that curcumin inhibits the proliferation induced by PMA and antiCD28 antibody or that induced by PHA of T lymphocytes isolated from healthy donors38. Yadav et al. (2005) reported that curcumin can suppress the phytohemagglutinin-induced proliferation of human peripheral blood mononuclear cells and inhibit IL-2 expression and NF-κB39. Desmodium gangeticum (L.) DC. (Fabaceae)

Desmodium gangeticum (L.) is a small shrub of tropical regions that has been used as a bitter tonic, febrifuge, digestive, anticatarrhal and antiemetic in inflammatory conditions of the chest and other organs. D. gangeticum has also been reported to contain alkaloids, flavone and isoflavanoid glycosides. Total alkaloids of this species showed anticholinesterase, smooth muscle stimulant, CNS stimulant and depressant responses. Mishra et al. (2005) has been reported that aminoglucosyl glycerolipid (9) of D. gangeticum possesses immunomodulatory activities. This compound exhibited in-vitro immunomodulatory activities, as it enhanced nitric oxide (NO) production and provided resistance against infection established in peritoneal macrophages by the protozoan parasite Leishmania donovani40. Eclipta prostrata (L.) L. (Asteraceae)

The methanol extract of Eclipta prostrata (syn. Eclipta alba) whole plant that contains 1.6% of wedelolactone showed immunomodulating effect in vivo. Administration of five doses (100 to 500 mg/kg body wt) significantly increased phagocytic index, antibody titer; F ratios of the phagocytic index and WBC count. Heighest linearity patterns of the doseresponse relationship were found in case of phagocytic index and lower in the case of antibody titer. In-vivo study showed that the aqueous extract of E. prostrata leaves significantly increased nonspecific immune response and lysozyme activity of the humoral responses in Oreochromis mossambicus41 Phyllanthus emblica L. (Euphorbiaceae)

Phyllanthus emblica (syn. Emblica officinalis) or ‘Amla’ is a small or medium size tree found in all

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deciduous forests of India. Amla fruits are largely used in Indian medicine. It is used as an acrid, diuretic, refrigerant, laxative, diarrhea and dysentery42. It is a popular ingredient of ‘Triphala’ and ‘Chyawanprash’. The anti-inflammatory response of E. officinalis extract has been well established and predicted mechanism for anti-inflammation is based on its function to reduce lymphocyte proliferation and histopathological severity of synovial hyperplasia43. Evolvulus alsinoides (L.) L. (Convolvulaceae)

Evolvulus alsinoides is an important and very popular plant in Ayurvedic system of medicine to improve intelligence, memory and higher mental fuctions. The immunomodulatory property of E. alsinoides extract was investigated and the result exposed that a remarkable reduction in inflammation and edema was observed. The extract also induced that nitric oxide synthase (NOS) significantly. At cellular level immunosuppression occurred during the early phase of the disease. There was mild synovial hyperplasia and infiltration of few mononuclear cells in the extract treated animals44. Ficus benghalensis L. (Moraceae)

Ficus benghalensis has been used by ayurvedic practitioners, in India to boost the immune system to fight a number of diseases. Gabhe et al. (2006) was investigate for immunomodulatory potential of various extracts of F. Benghalensis. The successive methanol and water extracts exhibited a significant increase in the percentage phagocytic responses and methanol extract was found to exhibit a dose related increase in the hypersensitivity reaction, to the sheep red blood cells antigen, at concentrations of 100 and 200 mg/kg. The methanol extract also significantly increased the antibody titer value dose dependently45. Glycyrrhiza glabra L. (Leguminosae)

The root extract of Glycyrrhiza glabra is used as a medicine for various diseases including antiinflammatory as well as anti-allergy46. It was investigated that crude polysaccharide fraction of the shoot and hairy root of G. glabra induced nitric oxide production by murine peritoneal macrophages invitro. In addition, the polysaccharide of G. glabra dose-dependently improved immune and antioxidant enzyme activities in mice. Glycyrrhizin (10) and βglycyrrhetinic acid (11) are the major components of G. glabra believed to have immunomodulatory properties. β-glycyrrhetinic acid has a potent inhibitory activity on the classical complement

pathway (IC50 = 35µM), but it has no inhibitory activity towards the alternative pathway (IC50 > 2500µM) 47. Hippophae rhamnoides L. (Elaeagnaceae)

Several reports have been made on immunomodulation of Hippophae rhamnoides L. (Seabuckthorn) using different types of immunomodulatory models. Alcoholic extracts of leaves and fruits of H. rhamnoides at 500 µg/ml concentrations were found to inhibit chromiuminduced free radical production, apoptosis, DNA fragmentation and restored the anti-oxidant status to that of control cells. The extract of leaf of H. rhamnoides also reported to possesses immunomodulatory activity through cellular and humoral immune response. Administration of leaf extract at 100 mg/kg dose along with chromium (Cr) significantly inhibited Cr-induced immunosuppression. The extract significantly inhibited Cr-induced reactive oxygen species generation and maintained the cell size identical to that of control cells. Cr treatment markedly inhibited the mitochondrial transmembrane potential by larger lymphocytes in particular, while the leaf extract restored the same significantly. The leaf extract at 100µg/ml alone stimulated IL-2 and IFN-γ production even in the absence of concanavalin A and also inhibited Cr-induced decline in IL-2 and IFN-γ production but it did not change IL-4 production. The ethanolic extract and of H. rhamnoides fruit and its flavones fraction have been reported to stimulate the production of interleukin-6 and tumor necrosis factoralpha (TNF-α) in peripheral blood mononuclear cells (PBMCs). The increased expressions of p-I κB, NFκB and p-p38 were observed with flavones fraction of H. rhamnoides fruit extract in human PBMCs with significantly suppressed expression of CD2548. Hydrastis canadensis L. (Ranunculaceae)

Hydrastis canadensis (Goldenseal) is indigenous to North America, and commonly used in conjunction with echinacea for the treatment of colds and flu. Sevaral reports have been published for its immunomodulatory activity. Root extract of H. canadensis showed antigen-specific in vivo immunomodulatory potential on rats that were injected with the novel antigen keyhole limpet hemocyanin. Berberine (12) alkaloid is thought to be the potent immunomodulator present in H. Canadensis. Berberine suppressed experimental autoimmune tubulointerstitial


nephritis in BALB/c mice at a daily dose of 10 mg/kg. It causes a decrease in the number of CD3 (+), CD4 (+), CD8 (+), and sIg (+) lymphocytes in comparison with tubulointerstitial nephritis mice. The same tendency was noticed in the lymphocytes from kidney infiltrates of treated animals. Berberine at 50 mg/kg for 5 days significantly decreased the mortality rate and attenuated tissue injury of the lungs and small intestine in mice challenged with lipopolysaccaride (LPS). The berberine also significantly reduced the plasma TNF-α, IFN-γ and NO levels, but did not suppress plasma IL12 levels in mice exposed to LPS49. Hypericum perforatum L. (Hypericaceae)

Hypericum perforatum (St. John's wort) is an ancient folk remedy, has been used as antiviral, antibacterial, anti-inflammatory, bruises, dysentery, jaundice, diarrhea, antidepressant and a wide range of other complaints. H. perforatum extract also reported to have immunomodulatory effect on cytokine-induced tryptophan degradation in human peripheral blood mononuclear cells and in the production of the immune activation marker neopterin. The lipophilic fraction of H. perforatum exerted immunosuppressing properties with respect to cellular and humoral immune response. Hyperforin (13) is the active component of H. perforatum which can stimulate IL-8 expression in human intestinal epithelia cells and primary hepatocytes. Hyperforin is also able to induce expression of mRNA, encoding another major inflammatory mediator-intercellular adhesion molecule-1. Hyperforin induced IL-8 mRNA through a xenobiotic receptor -independent transcriptional activation pathway50. Jatropha curcas L. (Euphorbiaceae)

The immunomodulatory effect of an 80% methanol extract of Jatropha curcas has been reported by AbdAlla et al. (2009). The extract showed stimulation of both humoral and cell-mediated seroresponse through increases of the antibody titers, lymphocyte and macrophage cells. Bioactivity guided activation of the extract was established to find out five componenets viz. di-C-glucoside, 6,6"-di-C-β-D-glucopyranosidemethylene-(8,8")-biapigenin (14), apigenin 7-O-β-Dneohesperidoside (15), apigenin 7-O-β-D-galactoside (16), orientin (17), vitexin (18). These compounds at 0.25 mg/kg dose showed immunostimulatory activity as a similar mechanism to that of the extract51. Mangifera indica L. (Anacardiaceae)

Mangifera indica is a medicinal plant traditionally used in tropical regions. M. indica is being used from

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many years to treat several disorders including anemia, hypotension, rheumatism gingivitis, diarrhea, dysentery, diabetes, asthma, infertility, lupus, prostatitis, prostatic hyperplasia, gastric disorders etc. Alcoholic extract of stem bark of Mangifera indica was studied for immunomodulatory activity on both the cell mediated as well as humoral immunity. Administration of the extract produced increase in humoral antibody (HA) titre and delayed type hypersensitivity (DTH) in mice. From these studies it can be shown that Mangifera indica has immunostimulatory activity. Mangiferin (19) is one of the most impotant molecules present in almost all parts of the plant viz. leaves, fruits, roots etc and it has been reported that mangiferine possesses immunomodulatory activity by increasing the production of IgG1 and IgG2b52. Matricaria chamomilla L. (Asteraceae)

Heteropolysaccharides of Matricaria chamomilla has been reported to have immunomodulatory activity. The immunomodulating activity of the heteropolysaccharides of M. chamomilla during air and immersion cooling was investigated by Uteshev et al. (1999). The polysaccharide was found to normalizd the developed the immune response upon air cooling and enhanced but do not normalized this process upon immersion cooling. The immunomodulating effect of the heteropolysaccharides upon cooling is attributed to initiation of immunostimulating properties of heavy erythrocytes, activization of immunoregulation cells of peripheral blood, and increased sensitivity of effector cells to helper signals. The effect of M. chamomilla and vaccination frequency on cattle immunization against rabies was reported by de Souza et al., (2008). There was no effect observed on treatment with M. chamomilla on cattle immunization against rabies; however, antibody titers were protective in cattle vaccinated twice, while 93.3% of cattle vaccinated only once had titers under 0.5 UI/ml after 60 days. The M. chamomilla did not alter the humoral immune response in cattle, and two vaccine doses are suggested for achieving protective antibody titers53. Mollugo verticillata L. (Molluginaceae)

Mollugo verticillata is a weed plant common in warm and/or wet regions of the American continent. The ethanolic extract of M. verticillata showed immunostimulatory activity in mice; when the

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peritoneal cells of mice were stimulated with Bacillus Calmette Guérin (BCG). But when mice peritoneal cells treated with the extract along with BCG showed a drastic reduction in NO production. The extract of M. verticillata directly increased NO release by peritoneal cells, but suppressed the immune response of these cells when treated with BCG antigen and Mycobacterium tuberculosis. Further analysis of the extract revealed that quercetin and triterpenoid glycosides are the probably responsible components for the effect of this plant material on the immune system54. Momordica charantia L. (Cucurbitaceae)

Momordica charantia (bitter melon) is a very popular plant in various systems of traditional medicine for several uses including anti-diabetic, anthelmintic, contraceptive, dysmenorrhea, eczema, anti-malarial, anti-gout, jaundice, leucorrhea, piles, pneumonia, psoriasis, cancer, immunomodulation, etc. The immunomodulatory activity of various components of bitter gourd, including peel, pulp, and seed, was assessed by measuring different parameters like IFN-γ, IL-4, etc. Two abortifacient proteins, α and β momorcharin have been isolated from the seeds of the M. charantia and it was found that noncytotoxic concentrations of these proteins significantly inhibited the mitogenic responses of mouse splenocytes to concanavalin A, phytohaemagglutinin and lipopolysaccharide in a dose-dependent manner. In addition, the alloantigeninduced lymphoproliferation and the in vitro generation of a primary cytotoxic lymphocyte response were severely suppressed in the presence of these proteins. Momorcharin is also able to decrease the functional capacity of macrophages and delayedtype hypersensitivity response as well as the humoral antibody formation to sheep red blood cells55. Morinda citrifolia L. (Rubiaceae)

Morinda citrifolia (Noni) has been used in folk remedies by polynesians for over 2000 yrs, and is reported to have a broad range of therapeutic effects, including antibacterial, antiviral, antifungal, antitumor, anthelmintic, analgesic, hypotensive, antiinflammatory, and immune enhancing effects. The alcoholic extract of M. citrifolia fruit various concentrations inhibited the production of tumor necrosis factor-alpha, (TNF-α).The alcoholic extract of M. citrifolia was found to contain a polysacchariderich substance that inhibited tumor growth through

activation of the host immune system. The extract was also capable of stimulating the release of several mediators from murine effector cells, including TNFα, interleukin-1beta (IL-1β), IL-10, IL-12, interferongamma (IFN-γ) and nitric oxide (NO) 56. Nelumbo nucifera Gaertn. (Nymphaeceae)

Nelumbo nucifera is a very known aquatic medicinal plant which has been used as a traditional medicine in India, China, Korea, Japan etc. from ancient time57. All most all parts of the plant have been reported for various pharmacological properties including hypoglycaemic, antidiarrhoeal, antimicrobial, diuretic, antipyretic, psychopharmacological, anti-inflammatory, anti-ischemic, antioxidant, hepatoprotective, etc. Very recently, it has been reported that hydro-alcoholic extract of N. nucifera rhizome and seed showed immunomodulatory potentials through altering the haematological parameters, enhanced phagocytosis, potentiated delayed type hypersensitivity in mice. The hydroalcoholic extract of seed and rhizome increased the total and differential leukocyte count and dosedependently potentiatiated the DTH reaction in mice. Furhter, in vitro study with both the extracts revealed that they have capability to stabilize the mesenteric mast ceels and erythrocytes membrane of Wister rats. The extracts also decreased the LPS- induced metric oxide production and expression of co-stimulatory molecules like CD40, CD80 and CD8658, 59, 60. Nerium oleander L. (Apocynaceae)

Nerium oleander is an ornamental plant and widely cultivated in Mosul (Iraq). There are several records are available of this plant that the plant can be used as arodenticid, insecticide, for indigestion, fever, leprosy, venereal diseases, etc. Al-Farwachi (2007) has been reported that the aqueous extract of N. oleander leaf exerts a prominent immunomodulatory effect on the rabbit’s immune system. The inhibitory and the stimulatory effect of the extract on the production of haemagglutination antibodies in the rabbits against SRBC have been observed with the extract treated animals. At the doses of 25, 50 and 75 mg/kg, a dose dependent inhibition of haemagglutination antibodies was observed from the result. In addition, the extract also inhibits the delayed type hypersensitivity reaction, phagocytic activity and percentage of nitro-blue tetrazolium positive cells61. Nigella sativa L. (Ranunculaceae)

The seeds and seed oil of Nigella sativa have been employed for thousands of years in folk medicine


throughout the world for the treatment and prevention of a number of diseases and conditions that include asthma, diarrhoea and dyslipidaemia, etc. The seed oil has been reported to have effect on immunomodulation. The oil showed significant decrease in splenocytes and neutrophils counts, but a rise in peripheral lymphocytes and monocytes in the experimental animals. Further, active principle components of seed oil of N. sativa was identified as thymoquinone (20) which possesses potent antiinflammatory effects on several inflammation-based models including experimental encephalomyelitis, colitis, peritonitis, oedama, and arthritis through suppression of the inflammatory mediators prostaglandins and leukotriens. Thymoquinine showed beneficial immunomodulatory properties through augmenting the T cell- and natural killer cellmediated immune responses62. Ocimum tenuiflorum L. (Labiatae)

Ocimum tenuiflorum (syn. O. sanctum) commonly known as ‘Tulsi’ has been extensively used in Ayurvedic system of medicine for various ailments and has been shown to possess significant adaptogenic/anti-stress properties. Different parts of the plant are claimed to be effective in a number of diseases. The fixed oil obtained from O. sanctum seeds is reported to possess significant antiinflammatory, antipyretic, analgesic and antiarthritic activities. A steam distilled extract of O. sanctum leaves has been shown to enhance anti-sheep red blood cells and IgE antibody titre. Alcoholic extract of O. sanctum showed immunomodulatory activity in both non-stressed as well as stressed animals. In nonstressed animals it was found that O. sanctum seed oil produced a significant increase in anti-SRBC antibody titre and caused a significant inhibition of antigen induced histamine release from the peritoneal mast cells. The oil also produced a significant reduction in foot pad thickness in mice and percentage leucocyte migration inhibition. It also has been repoted that hydroalcoholic extract of O. sanctum leaf at 10 mg/kg/day produced radioprotective activity in mice against 11Gy of Co60 γ- irradiation63. Plantago species (Plantago major L. & P. asiatica L. (Plantaginaceae)

A number of Plantago species especially Plantago major and Plantago asiatica (Plantaginaceae) have been used in the treatment of many ailments, viz. inflammation, infection, cancer and

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immunomodulation. The hot water extract of P. asiatica possessed significant inhibitory effect on the proliferation of lymphoma, carcinoma and on viral infection. P. major and P asiatica both exhibited dual effects of immunodulatory activity, enhancing lymphocyte proliferation and secretion of IFN-γ at low concentrations (< 50 µg/ml). These results indicated that hot water extracts of P. major and P. asiatica possess a broad-spectrum of antileukemia, anticarcinoma and antiviral activities, as well as activities which modulate cell-mediated immunity. Further several pure phytomolecules have been isolated from extract of P. major, i.e. aucubin (21), chlorgenic acid (22), ferulic acid (23), p-coumaric acid (24), vanilic acid (25), luteolin (26), baicalein (27). All these molecules are reported to possess a strong immunomodulatory activity on human peripheral blood mononuclear cells (PBMC) through lymphocyte transformation and secretion of IFN-γ using enzymelinked immunosorbent assay (ELISA) 64. Piper longum L. (Piperaceae)

Piper longum is an important medicinal plant, and is used in traditional medicine by many people in Asia and Pacific islands especially in Indian medicine. Piper longum is reported as good remedy for treating gonorrhea, menstrual pain, tuberculosis, sleeping problems, respiratory tract infections, chronic gut related pain and arthritic conditions. Alcoholic extract of the fruits of P. longum and its component piperine (28) was studies for their immunomodulatory activity. The report revealed that the extract as well as piperine increase the total WBC count, bone marrow cellularity. They also induce the number of α- esterase positive cells, total antibody production, total number of plaque forming cells. These effects may be due to the combined action of humoral and cell-mediated immune responses65. Premna tomentosa Willd. (Verbanaceae)

Premna tomentosa is widely used traditional medicinal plant. The leaves extract of this plant reported to stimulate immune system in response to Chromium (VI) induced immunosuppression in splenic lymphocytes. The leaves extract at pre-treated dose concentration of 500 µg/ml decreased cytotoxicity and reactive oxygen species level suppressed by Chromium treatment in lymphocyte cells culture. Further treatment of extract restored the antioxidant levels and lymphocyte proliferation similar to control cells66.

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Prunella vulgaris L. (Lamiaceae)

Prunella vulgaris is medicinal plant used in the traditional Chinese medicine for hundreds of years as a variety of ailments. Phytochemicals of this plant reported to modulate various immune factors like histamine, TNF-α, IgG, IgG1, IgG2b, NO, LTB4, IFN-γ, IL-2 and Src family protein kinase. Other Prunella species, P. laciniata was also reported to posse’s immunomodulating activity in vitro. The aquoues extract of both species stimulated T-lymphocytes proliferation and suppression of NO production by LPS-stimulated macrophages67. Psoralea corylifolia L. (Fabaceae)

P. corylifolia seed extract reported to shows immune stimulating property in mice. Administration of extract stimulates natural killer cell activity, antibody-dependent cellular cytotoxicity, antibodyforming cells and antibody complement-mediated cytotoxicity during tumor development. Lee & Kim (2008) was also reported that this plant extract modulating Th1/Th2 cytokine balance via inhibiting accumulation of eosinophils, upregulating the expression of IFN-γ and downregulating the expression of IL-4 in spleen cells culture medium68. Punica granatum L. (Family: Punicaceae)

Punica granatum fruits powder reported to stimulate cell-mediated immune response in rabbits. Oral administration of aqueous suspension of P. granatum fruits powder at a dose concentration of 100 mg/kg increased rabbit’s antibody titre against typhoid-H antigen and inhibited the migration of leucocytes69. Rhinacanthus nasutus (L.) Kurz (Acanthaceae)

It was demonstated that Rhinacanthus nasutus extract has immunomodulating property. Punturee et al. (2005) reported that the aquous and ethanol extract of R. nasutus significantly increased PBMC proliferation and the production of IL-2 and TNF-α in vitro. Whereas in vivo study revealed that the ethanol extract significantly increased the secondary antibody response in BALB/c mice. These results demonstared that the R. nasutus extract has immunomodulating activity with regards to non-specific cellular and humoral immunity32. Salvia officinalis L. (Lamiaceae)

Aerial parts of Salvia officinalis reported to rich mainly with polysaccharides including arabinogalactans, pectin and glucuronoxylan-related

polymers. The active fractions of these compounds showed immunomodulatory effects in the in vitro comitogenic thymocyte test. All the fractions increased rat thymocyte proliferation in order to glucuronoxylan-related polymers > pectin> arabinogalactans fractions. The pectin and arabinogalactans fractions also showed significant comitogenic effect with SIcomit/SImit ratio 3-4 indicated that these fractions have potential adjuvant properties70. Tamarindus indica L. (Leguminosae)

The tamarind (Tamarindus indica) is indigenous to Asian countries and widely cultivated in the American continents. The fruit pulp extract of T. indica traditionally used in spices, food components and juices etc in all over world. The fruit of T. indica is rich in polyphenols which have several potential uses like anti-atherosclerotic, antioxidant and immunomodulatory. A polysaccharide isolated from T. indica which showed immunomodulatory activities such as phagocytic enhancement, leukocyte migration inhibition and inhibition of cell proliferation. It has also been reported that hydro-alcoholic extract of fruit of T. indica inhibited the neutrophil reactive oxygen species generation, triggered by opsonized zymosan, n-formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetate and assessed by luminol- and lucigenin-enhanced chemiluminescence. The extract showed more effective inhibition of the PMAstimulated neutrophil function the opsonized zymosan. The extract also inhibited neutrophil NADPH oxidase activity, degranulation and elastase activity at concentrations higher than 200 µg/106 cells, without being toxic to the cells71. Further it has also been reported that the fruit pulp extract of T. indica blocked the increase of complement activity caused by the cholesterol-rich diet. The activity of 0.8 mg/ml of the extract on the classical/lectin pathways increased after 30 min of pre-incubation, while that of the alternative pathway decreased after 15 min at 1 mg/ml concentration of the extract72. Terminalia chebula Retz. (Combretaceae)

Terminalia chebula popularly known as ‘Myrobalan’ or ‘Haritaki’ is found mainly in the subHimalayan tracks and in all deciduous forests of India. Fruits are an important source of tannins. It is mainly used as an astringent, laxative, stomachic and tonic.it is an ingredient of ayurvedic preparation ‘Triphala’. The aqueous fruit extract of Terminalia


chebula has been investigated for its effect on cellmediated and humoral components of the immune system in mice. Administration of Terminalia chebula extract produced an increase in humoral antibody (HA) titer and delayed-type hypersensitivity (DTH) in mice. So it was concluded that the Terminalia chebula extract is a promising drug with immunostimulant properties73. Tinospora cordifolia (Willd.) Miers (Menispermaceae)

Immunomodulatory and antitumor actions of medicinal plant Tinospora cordifolia are mediated through activation of tumor-associated macrophages. Intraperitoneal administration of Tinospora cordifolia extract in tumour-bearing mice not only augments the basic function of macrophages such as phagocytosis but also their antigen presenting ability and secretion of IL-1, TNF-α and other cytokines. The aqueous extract of T. cordifolia exhibited boosting of phagocytic ability of macrophage in vitro at 5µg/ml. At the dose of 10 mg/kg (in vivo) the aqueous and ethanolic extracts of T. cordifolia significantly increased the antibody production against SRBC in animals when compared to control. The methanolic extract of T. cordifolia stem extract showed to increase the total WBC count, bone marrow cellularity(18.16×106/femur) and α-esterase positive cells (1423/4000 cells). The extract is also increased humoral immune response, by increasing the plaqueforming cells in the spleen and enhances macrophage activation. T. cordifolia extract reduced solid tumour growth and synergistically acted with cyclophosphamide in reducing the animal tumours74. Trigonella foenum-graecum L. (Fabaceae)

Trigonella foenum-graecum is a widely used medicinal and dietary herb through out of the world. Several biological potential of the plant has been reported including hypo-glycaemic, antiinflammatory, anti-allergic, etc. The aqueous extract of T. foenum has been evaluated for immunomodulatory activity by Hafeez et al. (2003). The result exposed that the extract at 50, 100 and 250 mg/kg doses significantly increased the relative organ weight of thymus and liver. The cellularities of thymus and bone marrow were also significantly increased at the same doses of the extract. A significant increase in the delayed type hypersensitivity response was monitored at doses of 50 and 100 mg/kg of the extract. At the dose of 100 mg/kg the extract showed humoral immunity as measured by plaque-forming cells. A significant

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increase in phagocytic index, phagocytic capacity of macrophages and lymphoproliferation assay was also observed with the extract treated animals75. Urtica dioica L. (Urticaceae)

Urtica dioica has been used as an adjuvant remedy in the treatment of arthritis form long time in Germany. The leaf and aerial parts of the plant extracts contains active compounds that reduce TNF-α and other inflammatory cytokines by inhibiting the genetic transcription factor. The major compounds like quercetin-3-O-rutinoside (29), kaempherol-3-Orutinoside (30) and isorhamnetin-3-O-glucoside (31) were isolated from the methanolic extract of the aerial parts of U. dioica and these components produced immunomodulatory activities in vitro by chemotaxis and intracellular killing activity (NBT reduction) tests. All compounds were determined to have significant chemotactic effects in 4, 8, 16 µg/ml doses. The results supported that the extract as well as its fraction could possibly be useful for treating patients suffering from neutrophil function deficiency and chronic granulomatous diseases76. Withania somnifera (L.) Dunal (cultivated var.) (Solanaceae)

Withania somnifera, commonly known as Indian ginseng, has been an important herb in the Ayurvedic and indigenous medical systems for over 3000 yrs. Different investigators have reported antiserotogenic, adaptogenic, anticancer and anabolic activity, and beneficial effects in the treatment of arthritis, geriatric problems, and stress. Withania somnifera has been revealed as immunostimulator and immunoregulator in immune inflammation animal models. It has been reported that administration of W. somnifera extract reduced leucopenia induced by cyclophosphamide (CP). This may be correlated as this extract could reduce the CP-induced toxicity and its usefulness in cancer therapy. There is an enhancement in the circulating antibody titre and the number of plaque forming cells in the spleen was observed after administration of W. somnifera extract. It was also found that Methanolic extract of W. somnifera exhibited radioprotective effect in normal BALB/c mice with increased bone marrow cellularity and reduction in chromosomal damage caused by sub lethal dose of gamma radiation. The level of IFN-γ, IL-2, and granulocyte macrophage colony-stimulating factor (GM-CSF) in normal BALB/c mice was found to increase in mice by administration of W. somnifera root extract. Withanolide (32) activated the murine

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Structures of some important phytoconstituents


macrophages, phagocytosis, and increased lysosomal enzymatic activity secreted by the macrophages, while also displaying anti-stress activity and positive effects on learning and memory in rats. Glycowithanolides and a mixture of sitoindosides IX and X isolated from WS were evaluated for their immunomodulatory and central nervous system effects (antistress, memory, and learning) in Swiss mice and Wistar strain albino rats77. Discussion The basic function of the immune system is to protect the individual against infectious agents and potential pathogens which puts the immune system in a vital position between a healthy and diseased state of a host. lmmunomodulators can be classified as immunoadjuvants, immunostimulants and immunosuppresants. lmmunoadjuvants are used to increase the efficacy of vaccines and since specific immunoadjuvants are used with specific vaccines, therefore could be considered as specific immunostimulants. lmmunostimulants by definition are inherently non-specific in nature as they are envisaged to enhances body's resistance against infection. They can act through innate immune response and through adaptive immune response. Immunosuppressants could be used for control pathological immune response and are active in autoimmune diseases, immediate & delayed type of hypersensitivity immune reactions and graft rejection78. Naturally produced medicinal plant products offer as an alternate immunomodulatory and therapeutic agents so as to overcome some of these hazards such as their non-availability in some developing countries, risk of misuse leading to drug resistance, environmental pollution and food residues and subsequently may be sustainable and environmentally acceptable. In clinical medicine, both aspects of immunomodulation viz. immunostimulation and immunosuppression are equally important. In conventional chemotherapy immunopotentiation is an ideal choice, when the host defense mechanisms are to be activated under conditions of impaired immune response79. In this article 55 medicinal plants, reported for their immunomodulatory activity have been reviewed. Several commonly used plants used in therapy with immunomodulatory activity included in this review are Allium sativum, Aloe vera, Andrographis paniculata, Azadirachta indica, Boerhaavia diffusa, Boswellia serrata, Curcuma longa, Centella asiatica,

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Carica papaya, Datura quercifolia, Emblica officinalis, Hydrastis Canadensis, Hypericum perforatum, Ocimum sanctum, Panax ginseng, Plantago major, Plantago asiatica, Piper longum, Tinospora cordifolia, Magnifera indica, Momordica charantia, Withania somnifera etc. Thease plants possess immunomodulatory effects through various mechanisms including their effect concerned with different cells like WBCs, macrophages, antigen presenting cells, mast cells, natural killer cells etc and co-stimulatory molecules in the body. The therapeutic and phytochemical aspects of this review revealed that the extracts of different plant species have prospective immunomodulatory effects through alteration of total and differential leukocyte count, delayed type hypersensitivity reaction, phagocytosis, mast cell protection, nitric oxide production, expression of co-stimulatory molecules etc. In addition, some extracts reduced the production of nitric oxide and expressed the co-stimulatory molecules (CD40, CD80 and CD86) significantly, which supports their effectiveness as immunomodulatory agents. The phytomolecules like andrographolide, asiaticoside, curcumin, glycyrrhizin, berberine, orientin, vitexin, mangiferin, piperine, withanolide and others have also been highlighted. Traditional significance of study to the society/researchers

The modulation of immune response through concept of rasayana in ayurveda is popular, where plants with rejuvenating activity have been described. Several plants have been identified as rasayanas in the Indian Ayurveda and other systems of medicine possessing various immuno-pharmcological properties such as immunostimulant, immunoadjuvant, neurostimulant, antiageing, antirheumatic, anticancer, adaptogenic, antistress, etc. This traditional knowledge with its holistic and systemetic approach supported by experimental evidances can serve as an innovative and powerful discovery engine for newer, safer and affordable medicines. Immunomodulation using traditional medicinal plants can provide an alternative to conventional chemotherapy for a variety of diseases, especially when host defence mechanism has to be activated under the conditions of impaired immune response or when a selective immunosuppression is desired in situations like autoimmune disorders. The concept of using rasayanas for health gets more credibility, when we realized that herbal antioxidants concurrently exhibit significant immunomodulatory

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activities. Thus this study represents perspective of the medicinal plants effective as immunomodulatory agents from natural resourses. Conclusion Major highlights of this review are on the description about immunomodulators from plant origin with phytochemical compounds and their relevance mechanism of action. This may help to recommend lead compounds from natural resources for drug development and establishing their efficacy from traditional resources. Several plants having potential immunomodulatory property have been discussed in this review, several other plants possessing similar type of activities have also been explored as natural immunomodulators. Thus, this review will not only help the researcher to know about natural immunostimulants but also will help to exploit several traditional medicines for drug discovery and development. Acknowledgement The authors are grateful to the Department of Science and Technology for financial support through India-Brazil-South Africa (IBSA) Trilateral Cooperation Program File No. INT/IBSA/0104/2010(i); dated 18/05/2011), Government of India, New Delhi. References 1 Sell S & Max EE, Immunology, Immunopathology Immunity, (ASM Press, USA), 2001. 2 Goldsby RA, Kindt TJ & Osborne BA, Kuby Immunology, (W.H. Freeman and Company, New York), 2006, 35-57. 3 Patwardhan B, Kalbag D, Patki PS & Nagsampagi BA, Search of immunomodulatory agents: a review, Ind Drugs, 28 (1990) 348-358. 4 Mukherjee PK & Wahile A, Perspectives of Safety for Natural Health Products, In: Herbal Drugs- A Twenty first Century Perspectives, edited by Sharma RK & Arora R, (Jaypee Brothers Medicinal Publishers Ltd., New Delhi), 2006, 50-59. 5 Mukherjee PK., Venkatesh M & Gantait A, Ayurveda in Modern Medicine: Development and Modification of Bioactivity, In: Comprehensive Natural Products Chemistry, (Elsevier Publications, The Netherlands). 2009. 6 Mukherjee PK, Nema NK, Venkatesh P & Debnath PK, Changing scenario for promotion and development of Ayurveda-way forward, J Ethnopharmacol, 143 (2012) 424-34. 7 Mukherjee PK & Houghton PJ, Evaluation of Herbal Medicinal Products-Perspectives of Quality, Safety and Efficacy, (Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, UK), 2009. 8 Mukherjee PK, Quality control of herbal drugs, (Business Horizons, New Delhi), 2002.

9 Mukherjee PK, GMP for Indian System of Medicine, In: GMP for Botanicals, edited by Verpoorte R & Mukherjee PK, (Business Horizons Ltd, New Delhi), 2003, 99-112. 10 Pandit S, Mukherjee PK, Ponnusankar S, Venkatesh M, Srikanth N, Metabolism mediated interaction of α- asarone and Acorus calamus with CYP3A4 and CYP2D6, Fitoterapia, 82 (2011) 369-74. 11 Mehrotra S, Mishra KP, Maurya R, Srimal RC, Yadav VS, Pandey R & Singh VK, Anticellular and immunosuppressive properties of ethanolic extract of Acorus calamus rhizome, Intl Immunopharmaco, 3 (2003) 53-61. 12 Duansak D, Somboonwong J & Patumraj S, Effects of Aloe vera on leukocyte adhesion and TNF-α and IL-6 levels in burn wounded rats, Clin Hemorheol Micro, 29 (2003) 239246. 13 Zhang X, Wang H, Song Y, Nie L, Wang L, Liu B, Shen P & Liu Y, Isolation, structure elucidation, antioxidative and immunomodulatory properties of two novel dihydrocoumarins from Aloe vera, Bioorg Med Chem Let, 16 (2006) 949-953. 14 Kyo E, Uda N, Kasuga S & Itakura Y, Immunomodulatory effects of aged garlic extract, JNUTR, 131 (2001) 1075S– 1079S. 15 Hodge G, Sandy H & Han P, Allium sativum (Garlic) Suppresses Leukocyte Inflammatory Cytokine Production in vitro: Potential Therapeutic Use in the Treatment of Inflammatory Bowel Disease, Cytometry, 48 (2002) 209-215. 16 Maiti K, Mukherjee K, Murugan V, Saha BP & Mukherjee PK, Enhancing bioavailability and hepatoprotective activity of andrographolide from Andrographis paniculata, a wellknown medicinal food, through its herbosome, J Sci Food Agric, 90 (2010) 43-51. 17 Chiou WF, Chen CF, Lin JJ, Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide, Br J Pharmacolol, 129 (2000) 1553-1560. 18 Upadhyay SN, Dhawan S, Garg S, & Talwar GP, Immunomodulatory effects of neem (Azadirachta indica) oil, Int Immunopharmacol, 14 (1992) 1187-1193. 19 Kaur GS, Alam M & Athar M, Nimbidin suppresses functions of macrophages and neutrophils: relevance to its antiinflammatory mechanisms, Phytother Res, 18 (2004) 4194-24. 20 Muruganadan S, Garg H, Lal J, Chandra S & Kumar D, Studies on the immunostimulant and antihepatotoxic activities of Asparagus racemosus root extract, J Medic Arom Plant Sci, 22 (2000) 9-52. 21 Gokhale AB, Damre AS & Saraf MN, Investigations into the immunomodulatory activity of Argyreia speciosa, J Ethnopharmacol, 84 (2003)109-114. 22 Patil KS, Jalalpure SS & Wadekar RR. Effect of Baliospermum montanum Root Extract on Phagocytosis by Human Neutrophils, Ind J Pharm Sci, 71 (2009) 68-71. 23 Chang SL, Chiang YM, Chang CLT, Yeh HH, Shyur LF, Kuo YH, Wu TK & Yang WC, Flavonoids centaurein and centaureidin from Bidens pilosa stimulate IFN-α expression, J Ethnopharmacol, 112 (2007) 232-236. 24 Mehrotra S, Mishra KP, Maurya R, Srimal RC & Singh VK, Immunomodulation by ethanolic extract of Boerhaavia diffusa roots, Int Immunopharmacol 2 (2002) 987-996.


25 Pandey R, Maurya R, Singh G, Sathiamoorthy B & Naik S, Immunosuppressive properties of flavonoids isolated from Boerhaavia diffusa Linn., Int Immunopharmacol, 5 (2005) 541-553. 26 Sharma ML, Kaul A, Khajuria A, Singh S & Singh GB, Immunomodulatory Activity of Boswellic Acids (Pentacyclic Triterpene Acids) from Boswellia serrata, Phytother Res, 10 (1998) 107-112. 27 Maity N, Nema NK, Mukherjee PK & Sarkar BK, Antiwrinkle potential of standardized flower extract of Calendula officinalis L., Pharm Biol, 50 (2012) 556-557. 28 Jimenez ME, Garcia LA & Paco L, A new extract of the plant Calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation, BMC Cancer, 6 (2006) 6-8. 29 Zvetkova E, Wirleitner B, Tram NT, Schennach H & Fuchs D, Aqueous extracts of Crinum latifolium (L.) and Camellia sinensis show immunomodulatory properties in human peripheral blood mononuclear cells, Int Immunopharmacol, 1 (2001) 2143-2150. 30 Ghule BV, Murugananthan G, Nakhat PD & Yeole PG, Immunostimulant effects of Capparis zeylanica Linn. Leaves, J Ethnopharmacol 108 (2006) 311-315. 31 Otsuki N, Dang NH, Kumagai E, Kondo A, Iwata S & Morimoto C, Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects, J Ethnopharmacol 127 (2010) 760-767. 32 Punturee K, Wild CP, Kasinrerk W & Vinitketkumnuen U, Immunomodulatory activities of Centella asiatica and Rhinacanthus nasutus extracts, Asian Pac Org Cancer Prev, 6 (2005) 396-400. 33 Song JY, Yang HO, Pyo SN, Jung S, Yi SY & Yun YS, Immunomodulatory Activity of Protein-Bound Polysaccharide Extracted from Chelidonium majus, Archives Pharm Res, 25 (2002) 158-164. 34 Lee DY, Choi G, Yoon T, Cheon MS, Choo BK & Kim HK, Anti-inflammatory activity of Chrysanthemum indicum extract in acute and chronic cutaneous inflammation, J Ethnopharmacol, 123 (2009).149-154. 35 Kim JH, Mun YJ, Woo WH, Jeon KS, An NH & Park JS, Effects of the ethanol extract of Cichorium intybus on the immunotoxicity by ethanol in mice, Int Immunopharmacol, 2 (2002) 733-744. 36 Gharagozloo M & Ghaderi A, Immunomodulatory effect of concentrated lime juice extract on activated human mononuclear cells, J Ethnopharmacol, 77 (2001) 85-90. 37 Kaul A, Bani S, Zutshi U, Suri KA, Satti NK & Suri OP, Immunopotentiating properties of Cryptolepis buchanani root extract. Phytother Res, 17 (2003) 1140-1144. 38 Ranjan D, Chen C, Johnston TD, Jeon H & Nagabhushan M, Curcumin blocks cyclosporine A-resistant CD28 costimulatory pathway of human T-cell proliferation. J Surg Res, 77 (1998) 174-178. 39 Yadav VS, Mishra KP, Singh DP, Mehrotra S & Singh VK, Immunomodulatory effects of curcumin, Immunopharmacol Immunotoxicol, 27 (2005) 485-497. 40 Mishra PK, Singh N, Ahmad G, Dube A & Maurya R, Glycolipids and other constituents from Desmodium gangeticum with antileishmanial and immunomodulatory activities, Bioorg Med Chem Lett, 15 (2005) 4543-4536.

255

41 Christybapita D, Divyagnaneswari M & Dinakaran Michael R, Oral administration of Eclipta alba leaf aqueous extract enhances the non-specific immune responses and disease resistance of Oreochromis mossambicus. Fish Shellfish Immun, 23 (2007) 840-852. 42 Ponnusankar S, Pandit S, Babu R, Bandyopadhyay A & Mukherjee PK, Cytochrome P 450 inhibitory potential of triphla-a rasayana from Ayurveda, J Ethnopharmacol, 133 (2011) 120-125. 43 Sairam K, Rao CV, Babu MD, Kumar KV, Agrawal VK & Goel RK, Antiulcerogenic effect of methanolic extract of Emblica officinalis: An experimental study, J Ethnopharmacol, 82 (2002) 1-9. 44 Ganju L, Karan D, Chanda, S, Srivastava, KK, Sawhney RC & Selvamurthy W, Immunomodulatory effects of agents of plant origin, Biomed Pharmacother, 57 (2003) 296-300. 45 Gabhe SY, Tatke PA & Khan TA, Evaluation of the immunomodulatory activity of the methanol extract of Ficus benghalensis roots in rats, Indian J Pharmacol, 38 (2006) 271-275. 46 Pandit S, Bandyopadhyay A, Ponnusankar S, Ota S & Mukherjee PK, Exploring the possible metabolism mediated interaction of Glycyrrhiza glabra extract with CYP3A4 and CYP2D6, Phytotherapy Res, 25 (2011) 1429-1434 47 Hong YK, Wu HT, Ma T, Liu WJ & He XJ, Effects of Glycyrrhiza glabra polysaccharides on immune and antioxidant activities in high-fat mice, Int J BioMacro, 45 (2009) 61-64. 48 Geetha S, Singh V, Ram MS, Ilavazhagan G, Banerjee PK & Sawhney RC, Immunomodulatory effects of seabuckthorn (Hippophae rhamnoides L.) against chromium (VI) induced immunosuppression, Mol Cell Biochem, 278 (2005) 101-109. 49 Li F, Wang HD, Lu DX, Wang YP, Qi RB, Fu YM & Li CJ, Neutral sulfate berberine modulates cytokine secretion and increases survival in endotoxemic mice, Acta Pharmacol Sinic, 27 (2006) 1199-1205. 50 Zhou C, Tabb MM, Sadatrafiei A, Grün F, Sun A & Blumberg B, Hyperforin, the active component of St. John's wort, induces IL-8 expression in human intestinal epithelial cells via a MAPK-dependent, NF-kappaB-independent pathway, J Clin Immunol 24 (2004) 623-636. 51 Abd-Alla HI, Moharram FA, Gaara AH & El-Safty MM, Phytoconstituents of Jatropha curcas L. leaves and their immunomodulatory activity on humoral and cell-mediated immune response in chicks. Zeitsschriftfur Narurforshhung, J Biosciences, 64 (2009) 495-501. 52 García D, Leiro J, Delgado R, Sanmartín ML & Ubeira FM, Mangifera indica L. extract (Vimang) and mangiferin modulate mouse humoral immune responses, Phytother Res, 17 (2003) 1182-1187. 53 De Souza RLS, Frazatti-Gallina NM, De Lima, PR, Giuffrida R, Albas A, Oba E & Pardo PE, Efficiency of Matricaria chamomilla CH12 and number of doses of rabies vaccine on the humoral immune response in cattle, J Vet Sci, 9 (2008) 433-435. 54 Ferreira AP, Soares GL, Salgado CA, Gonçalves LS., Teixeira FM, Teixeira HC & Kaplan MA, Immunomodulatory activity of Mollugo verticillata L, Phytomedicine, 10 (2003) 154-158. 55 Pongnikorn S, Fongmoon D, Kasinrerk W & Limtrakul PN, Effect of bitter melon (Momordica charantia Linn) on level

256

56

57

58

59

60

61

62

63

64

65

66

67


and function of natural killer cells in cervical cancer patients with radiotherapy, J Med Assoc Thiland, 86 (2003) 61-68. Hirazumi A & Furusawa E, An immunomodulatory polysacchariderich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity, Phytother Res, 13 (1999) 380-387. Mukherjee PK, Mukherjee D, Maji AK, Rai S & Heinrich M, The sacred lotus (Nelumbo nucifera) - Phytochemical and therapeutic profile, J Pharm Pharmacol, 61 (2009b) 407422. Mukherjee PK, Saha K, Das J, Pal M & Saha BP, Studies on the anti-inflammatory activity of rhizomes of Nelumbo nucifera, Planta Med, 63 (1997) 367-369. Mukherjee D, Khatua TN, Venkatesh P, Saha BP & Mukherjee PK, Immunomodulatory potential of rhizome and seed extracts of Nelumbo nucifera Gaertn, J Ethnopharmacol, 128 (2010a) 490-94. Mukherjee D, Biswas A, Bhadra S, Venkatesh P, Biswas T, Saha BP & Mukherjee PK,. Exploring the potential of Nelumbo nucifera rhizome on membrane stabilization, mast cell protection, nitric oxide synthesis, and expression of costimulatory molecules, Immunopharmacol Immunotoxicolcol, 32 (2010b) 466–472. Al-Farwachi, In vitro and in vivo immunomodulatory activities of Nerium oleander aqueous leaf extract in rabbits, J Ani Vet Adv, 6 (2007) 1047-1050. Salem ML, Immunomodulatory and therapeutic properties of the Nigella sativa L. seed, Int Immunopharmacol 5 (2005) 1749-1770. Mediratta PK, Sharma KK & Singh S, Evaluation of immunomodulatory potential of Ocimum sanctum seed oil and its possible mechanism of action, J Ethnopharmacol, 80 (2002) 15-20. Chiang LC, Ng LT, Chiang W, Chand MY & Lin CC, Immunomodulatory activities of flavonoids, monoterpenoids, Iridoid glycosides and phenolic compounds of plantago species, Planta Med, 69 (2003b) 600-604. Sunila ES & Kuttan G, Immunomodulatory and antitumor activity of Piper longum Linn. and piperine, J Ethnopharmacol, 90 (2004) 339-346. Pandima DK, Sai Ram M, Sreepriya M, Ilavazhagan G & Devaki T, Immunomodulatory effects of Premna tomentosa extract against Cr (VI) induced toxicity in splenic lymphocytes-an in vitro study, Biomed Pharmacother, 57 (2003) 105-108. Harput US, Saracoglu I & Ogihara Y, Effects of two Prunella species on lymphocyte proliferation and nitric oxide production, Phytother Res, 20 (2006) 157-159.

68 Lee YC & Kim SH, Immunomodulatory effect of Juglans sinensis, Psoralea corylifolia, Cheong-a-hwan extract and cyclosporine A on Th1(IFN-γ)/Th2(IL-4) cytokine balance, eosinophil accumulation in a murine model of asthma, Phytochem Let, 1 (2008) 6-10. 69 Ross GR, Selvasubramanian S & Jayasundar S, Immunomodulatory activity of Punica granatum in rabbits a preliminary study, J Ethnopharmacol, 78 (2001) 85-87. 70 Capek P, Hribalova V, Svandova E, Ebringerova A, Sasinkova V & Masarova J, Characterization of immunomodulatory polysaccharides from Salvia officinalis L., Int J Bil Macromol, 33 (2003) 113-119. 71 Sreelekha TT, Vijayakumar, T, Ankanthil R, Vijayan KK & Nair MK, Immunomodulatory effects of a polysaccharide from Tamarindus indica, Anticancer, 4 (1993) 209-212. 72 Librandi APL, Chrysóstomo TN, Azzolini AECS, Recchia CGV, Uyemura SA & Pandochi AIA, Effect of the extract of the tamarind (Tamarindus indica) fruit on the complement system: Studies in vitro and in hamsters submitted to a cholesterol-enriched diet, Food Chem Toxicol, 45 (2007) 1487-1495. 73 Shivaprasad HN, Kharya MD, Rana AC, Mohan S, Preliminary Immunomodulatory Activities of the Aqueous Extract of Terminalia chebula, Pharm Biol, 44 (2006) 32-34. 74 Bishayi B, Roychowdhury S, Ghosh S & Sengupta M, Hepatoprotective and immunomodulatory properties of Tinospora cordifolia in CCl4 intoxicated mature albino rats, J Toxicol Sci, 27 (2002) 139-146. 75 Hafeez BB, Haque R, Parvez S, Pandey S, Sayeed I & Raisuddin S, Immunomodulatory effects of fenugreek (Trigonella foenum graecum L.) extract in mice, Int Immunopharmacol, 3 (2003) 257-265. 76 Akbay P, Basaran AA, Undege U & Basaran N, In vitro immunomodulatory activity of flavonoid glycosides from Urtica dioica L, Phytother Res, 17 (2003) 34- 37. 77 Ghosal S, Lal J, Srivastava R, Bhattacharya SK, Upadhyay SN, Jaiswal AK, Chattopadhyay U, Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera, Phytother Res, 3 (1989) 201-206. 78 Allison AC, Immunological adjuvants and their mode of action. Arch Immunol Therap Exp, 45 (1997) 141-147. 79 Chatterjee R K, Fatmma N, Jain RK, Gupta CM, Anand N, Litomoides carinii in rodents: Immunomodulation in potentiating action of diethylecarbamazepine. Jpn J Exp Med, 58 (1988) 243-248.

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