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 Bhadra

1, D Mukherjee

1, Fernão C Braga

2 & Motlalepula G Matsabisa

3

1School 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

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’ ______________

*Corresponding author

INDIAN J TRADITIONAL KNOWLEDGE, VOL. 13, NO. 2, APRIL 2014

236

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-

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

Fig. 1Mechanism of immunomodulation

MUKHERJEE et al.: MEDICINAL PLANTS AS IMMUNOMODULATOR

237

Table 1Medicinal plants possessing immunomodulatory properties(Cond.)

Sl No. Plant name Parts used Immunomodulatory mechanism References

1. Eclipta prostrata (L.) L.

(Asteraceae)

Whole plant Induces phagocytic index, antibody titer of mice

Increase non-specific immune response and lysosomal

activity of the humoral responses

41

2. Phyllanthus emblica L.

(Euphorbiaceae)

Fruits Imunosuppressive effects on lymphocyte proliferation

Restoration of IL-2 and IFN- γ production

43

3. Evolvulus alsinoides (L.) L.

(Convolvulaceae)

Whole plant Decreases the level of nitric oxide synthase (NOS)

Exert adaptogenic properties

44

4. Ficus benghalensis L.

(Moraceae)

Whole plant Enhance the phagocytosis of the human

neutrophils in vitro

Increase the antibody titer value

45

5. Glycyrrhiza glabra L.

(Leguminosae)

Bark & root Enhanced immune and antioxidant enzyme activities

Stimulates immune cells by CD69 expression on CD4

and CD8 T cells and macrophages function

46, 47

6. Hippophae rhamnoides L

. (Elaeagnaceae)

Leaves & fruits Inhibits chromium-induced free radical production,

apoptosis, DNA fragmentation

Stimulates IL-2 and IFN-γ production

48

7. Hydrastis canadensis L.

(Ranunculaceae)

Root Reduces plasma TNF-α, IFN- γ and NO levels

Inhibits the T helper -type 2 cytokine profile

49

8. Hypericum perforatum L.

(Hypericaceae)

Aerial parts Increase candidacidal activity of neutrophils and

decreased adhesion function of epithelial cells

Alter the function of NF-kB

50

9. Jatropha curcas L.

(Euphorbiaceae)

Leaves Increase the antibody titers, lymphocyte and

macrophage cells

51

10. Mangifera indica L.

(Anacardiaceae)

Fruits Increase in humoral antibody (HA) titre and DTH

Enhance production of IgG1 and IgG2b

52

11. Matricaria chamomilla L.

(Asteraceae)

Flowers Activation of immune cells of peripheral blood, and

increased sensitivity of effector cells to helper signals

53

12. Mollugo verticillata L.

(Molluginaceae)

Leaves Inhibits the production of NO 54

13. Momordica charantia L.

(Cucurbitaceae)

Fruits & seeds Inhibits the release of TNF-α, NO and proliferation of

spleen cells induced by PHA and Con A

55

14. Morinda citrifolia L.

(Rubiaceae)

Fruits Stimulating the release TNF-α, IL-β, IL-10, IL-12,

IFN-γ

56

15. Nelumbo nucifera

Gaertn.(Nymphaeceae)

Rhizome & seed Reduce NO production, protects mast cells

degranulation

Express CD40, CD80, CD86

59,60

16. Nerium oleander L.

(Apocynaceae)

Leaves Inhibited haemaglutination antibodies, DTH reaction,

phagocytic index etc in mice

61

17. Nigella sativa L.

(Ranunculaceae)

Seeds 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

62

18. Ocimum tenuiflorum L.

(Labiatae)

Aerial parts Inhibits antigen induced histamine release from the

peritoneal mast cells, foot pad thickness and leucocyte

migration

63

19. Plantago species (Plantago major L.

& P. asiatica L. (Plantaginaceae)

Seed 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.

64

20. Piper longum L.

(Piperaceae)

Fruits & leaves Increase the total WBC count, bone marrow

cellularity, α- esterase positive cells, enhance the total

antibody production

65

(Table 1-Contd.)


238

Table 1Medicinal plants possessing immunomodulatory properties


21. Acorus calamus L. (Araceae) Rhizome Increase the production of IL-2, tumor necrosis factor

(TNF)-α

11

22. Aloe vera (L.) Burm.f.

(Asphodelaceae)

Leaves Increases phagocytosis and stimulating the production

of superoxide

12, 13

23. Allium sativum L. (Alliaceae) Fruits Suppress leukocyte inflammatory cytokine production 14,15

24. Andrographis paniculata Wall. ex

Nees (Acanthaceae)

Aerial parts Increase the production of IL-2, Inhibits of NO

production

17

25. Azadirachta indica A. Juss.

(Meliaceae)

Leaves Increase IgM and IgG production

Inhibits of NO synthesis, degranulation of neutrophils

18

26. Asparagus racemosus Willd

(Liliaceae)

Root Increase the production of leucocytosis

Enhances the phagocytic activity of the macrophages

20

27. Argyreia speciosa (L. f.) Sweet

(Convolvulaceae)

Root & seeds Enhance the production of circulating antibody titre

Increase in DTH reaction

21

28. Baliospermum montanum (Willd.)

Müll.Arg. (Euphorbiaceae)

Root & leaves Enhances neutrophil phagocytic function such as

neutrophil locomotion, chemotaxis

Stabilized mast cell degranulation induced by

compound 48/80.

22

29. Bidens pilosa L. (Asteraceae) Whole plant Enhances the cytokine production and white blood

cells population

Increases IFN-γ promoter activity

23

30. Boerhaavia diffusa L.

(Nyctaginaceae)

Root Inhibits human NK cell cytotoxicity in vitro

Inhibits production of NO, IL-2 and TNF-α

24

31. Boswellia serrata Roxb. ex Colebr.

(Burseraceae)

Bark Inhibits passive paw anaphylaxis reaction and mast

cells protection

26

32. Calendula officinalis L.

(Asteraceae)

Leaves & flowers Inhibits tumor cell proliferation 28

33. Camellia sinensis (L.) Kuntze

(Theaaceae)

Leaves Enhances the neopterin production in peripheral

mononuclear cells

29

34. Capparis zeylanica L

(Capparidaceae)

Leaves Prevents myelosupression in mice with

cyclophosphamide and potentiats DTH reaction

30

35. Carica papaya L.

(Caricaceae)

Leaves & seeds It enhances the phytohemagglutinin responsiveness of

lymphocytes

It inhibits the classical complement-mediated

hemolytic pathway

31

36. Centella asiatica (L.)

Urban. (Umbelliferae)

Leaves 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

32

37. Chelidonium majus L.

(Papaveraceae)

Aerial parts Exert antitumor immunostimulatory effect 33

38. Chrysanthemum indicum L.

(Compositae)

Aerial parts Increases DTH reaction, antibody generation,

Potentiates the mononuclear phagocytosis function

34

39. Cichorium intybus L.

(Asteraceae)

Root Increases DTH reaction, phagocytic activity and

natural killer (NK) cell activity and IFN-γ secretion

35

40. Citrus aurantiifolia (Christm.)

Swingle (Rutaceae)

Fruits & leaves Inhibits proliferation of PHA activated mononuclear

cells, staphylococcal protein

36

41. Cryptolepis dubia (Burm.f.)

M.R.Almeida. (Apocynaceae)

Root It stimulates the DTH reaction and also increases the

humoral antibody production

37

42. Curcuma longa L.

(Zingiberaceae)

Rhizome 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

38,39

43. Desmodium gangeticum (L.) DC.

(Fabaceae)

Whole plant Enhance NO production and provided resistance

against infection established in peritoneal macrophages

by the protozoan parasite Leishmania donovani

40

(Table 1-Contd.)


239

Table 1Medicinal plants possessing immunomodulatory properties


44. Acorus calamus L. (Araceae) Rhizome Increase the production of IL-2, tumor necrosis factor

(TNF)-α

11

45. Aloe vera (L.) Burm.f.

(Asphodelaceae)

Leaves Increases phagocytosis and stimulating the production

of superoxide

12, 13

46. Allium sativum L. (Alliaceae) Fruits Suppress leukocyte inflammatory cytokine production 14,15

47. Andrographis paniculata Wall. ex

Nees (Acanthaceae)

Aerial parts Increase the production of IL-2, Inhibits of NO

production

17

48. Azadirachta indica A. Juss.

(Meliaceae)

Leaves Increase IgM and IgG production

Inhibits of NO synthesis, degranulation of neutrophils

18

49. Asparagus racemosus Willd

(Liliaceae)

Root Increase the production of leucocytosis

Enhances the phagocytic activity of the macrophages

20

50. Argyreia speciosa (L. f.) Sweet

(Convolvulaceae)

Root & seeds Enhance the production of circulating antibody titre

Increase in DTH reaction

21

51. Baliospermum montanum (Willd.)

Müll.Arg. (Euphorbiaceae)

Root & leaves Enhances neutrophil phagocytic function such as

neutrophil locomotion, chemotaxis

Stabilized mast cell degranulation induced by

compound 48/80.

22

52. Bidens pilosa L. (Asteraceae) Whole plant Enhances the cytokine production and white blood

cells population

Increases IFN-γ promoter activity

23

53. Boerhaavia diffusa L.

(Nyctaginaceae)

Root Inhibits human NK cell cytotoxicity in vitro

Inhibits production of NO, IL-2 and TNF-α

24

54. Boswellia serrata Roxb. ex Colebr.

(Burseraceae)

Bark Inhibits passive paw anaphylaxis reaction and mast

cells protection

26

55. Calendula officinalis L.

(Asteraceae)

Leaves & flowers Inhibits tumor cell proliferation 28

56. Camellia sinensis (L.) Kuntze

(Theaaceae)

Leaves Enhances the neopterin production in peripheral

mononuclear cells

29

57. Capparis zeylanica L

(Capparidaceae)

Leaves Prevents myelosupression in mice with

cyclophosphamide and potentiats DTH reaction

30

58. Carica papaya L.

(Caricaceae)

Leaves & seeds It enhances the phytohemagglutinin responsiveness of

lymphocytes

It inhibits the classical complement-mediated

hemolytic pathway

31

59. Centella asiatica (L.)

Urban. (Umbelliferae)

Leaves 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

32

60. Chelidonium majus L.

(Papaveraceae)

Aerial parts Exert antitumor immunostimulatory effect 33

61. Chrysanthemum indicum L.

(Compositae)

Aerial parts Increases DTH reaction, antibody generation,

Potentiates the mononuclear phagocytosis function

34

62. Cichorium intybus L.

(Asteraceae)

Root Increases DTH reaction, phagocytic activity and

natural killer (NK) cell activity and IFN-γ secretion

35

63. Citrus aurantiifolia (Christm.)

Swingle (Rutaceae)

Fruits & leaves Inhibits proliferation of PHA activated mononuclear

cells, staphylococcal protein

36

64. Cryptolepis dubia (Burm.f.)

M.R.Almeida. (Apocynaceae)

Root It stimulates the DTH reaction and also increases the

humoral antibody production

37

65. Curcuma longa L.

(Zingiberaceae)

Rhizome 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

38,39

66. Desmodium gangeticum (L.) DC.

(Fabaceae)

Whole plant Enhance NO production and provided resistance

against infection established in peritoneal macrophages

by the protozoan parasite Leishmania donovani

40

(Table 1-Contd.)


240



67. Eclipta prostrata (L.) L.

(Asteraceae)

Whole plant Induces phagocytic index, antibody titer of mice

Increase non-specific immune response and lysosomal

activity of the humoral responses

41

68. Phyllanthus emblica L.

(Euphorbiaceae)

Fruits Imunosuppressive effects on lymphocyte proliferation

Restoration of IL-2 and IFN- γ production

43

69. Evolvulus alsinoides (L.) L.

(Convolvulaceae)

Whole plant Decreases the level of nitric oxide synthase (NOS)

Exert adaptogenic properties

44

70. Ficus benghalensis L.

(Moraceae)

Whole plant Enhance the phagocytosis of the human

neutrophils in vitro

Increase the antibody titer value

45

71. Glycyrrhiza glabra L.

(Leguminosae)

Bark & root Enhanced immune and antioxidant enzyme activities

Stimulates immune cells by CD69 expression on CD4

and CD8 T cells and macrophages function

46, 47

72. Hippophae rhamnoides L

. (Elaeagnaceae)

Leaves & fruits Inhibits chromium-induced free radical production,

apoptosis, DNA fragmentation

Stimulates IL-2 and IFN-γ production

48

73. Hydrastis canadensis L.

(Ranunculaceae)

Root Reduces plasma TNF-α, IFN- γ and NO levels

Inhibits the T helper -type 2 cytokine profile

49

74. Hypericum perforatum L.

(Hypericaceae)

Aerial parts Increase candidacidal activity of neutrophils and

decreased adhesion function of epithelial cells

Alter the function of NF-kB

50

75. Jatropha curcas L.

(Euphorbiaceae)

Leaves Increase the antibody titers, lymphocyte and

macrophage cells

51

76. Mangifera indica L.

(Anacardiaceae)

Fruits Increase in humoral antibody (HA) titre and DTH

Enhance production of IgG1 and IgG2b

52

77. Matricaria chamomilla L.

(Asteraceae)

Flowers Activation of immune cells of peripheral blood, and

increased sensitivity of effector cells to helper signals

53

78. Mollugo verticillata L.

(Molluginaceae)

Leaves Inhibits the production of NO 54

79. Momordica charantia L.

(Cucurbitaceae)

Fruits & seeds Inhibits the release of TNF-α, NO and proliferation of

spleen cells induced by PHA and Con A

55

80. Morinda citrifolia L.

(Rubiaceae)

Fruits Stimulating the release TNF-α, IL-β, IL-10, IL-12,

IFN-γ

56

81. Nelumbo nucifera

Gaertn.(Nymphaeceae)

Rhizome & seed Reduce NO production, protects mast cells

degranulation

Express CD40, CD80, CD86

59,60

82. Nerium oleander L.

(Apocynaceae)

Leaves Inhibited haemaglutination antibodies, DTH reaction,

phagocytic index etc in mice

61

83. Nigella sativa L.

(Ranunculaceae)

Seeds 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

62

84. Ocimum tenuiflorum L.

(Labiatae)

Aerial parts Inhibits antigen induced histamine release from the

peritoneal mast cells, foot pad thickness and leucocyte

migration

63

85. Plantago species (Plantago major L.

& P. asiatica L. (Plantaginaceae)

Seed 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.

64

86. Piper longum L.

(Piperaceae)

Fruits & leaves Increase the total WBC count, bone marrow

cellularity, α- esterase positive cells, enhance the total

antibody production

65

(Table 1-Contd.)


241

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

.

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

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

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

.

Azadirachta indica A. Juss. (Meliaceae)

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 anti-

inflammatory, 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



87. Premna tomentosa Willd.

(Verbanaceae)

Stem bark Decrease the lymphocyte proliferation and antioxidant

levels

66

88. Prunella vulgaris L.

(Lamiaceae)

Fruits Stimulates the proliferation of T-lymphocytes and

suppressed NO production in lipopolysaccharide-

stimulated macrophages

67

89. Psoralea corylifolia L.

(Fabaceae)

Leaves Up regulates the production of OVA-specific Th1

cytokine (IFN-γ) and down regulated OVA-specific

Th2 cytokine

68

90. Punica granatum L.

(Punicaceae)

Fruits Inhibits the leucocyte migration 69

91. Rhinacanthus nasutus (L.) Kurz.

(Acanthaceae)

Whole plant Increased the production of IL-2 and TNF-α 33

92. Salvia officinalis L.

(Lamiaceae)

Aerial parts Induce rat thymocyte proliferation 70

93. Tamarindus indica L. (Leguminosae) Fruits Inhibits the phorbol myristate acetate (PMA)

stimulated neutrophil function, neutrophil NADPH

oxidase activity, and elastase activity

71,72

94. Terminalia chebula Retz.

(Combretaceae)

Fruits Increase in HA titer and DTH reaction 73

95. Tinospora cordifolia (Willd.) Miers

(Menispermaceae)

Stem & root Increase the total white blood cell count, bone marrow

cellularity and α-esterase positive cells

Enhance the macrophage activation

74

96. Trigonella foenum-graecum L.

(Fabaceae)

Seeds Increases the phagocytic index and phagocytic

capacity of macrophages, enhancement of thymus and

bone marrow cellularities

75

97. Urtica dioica L.

(Urticaceae)

Aerial parts Reduce TNF-α and other inflammatory cytokines by

inhibiting the genetic transcription factor

76

98. Withania somnifera (L.) Dunal

(cultivated var.) (Solanaceae)

Root Increase total WBC count, bone marrow cellularity,

circulating antibody titer, plaque forming cells in the

spleen, phagocytic activity of macrophages

77


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-12-

myristate-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


243

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

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


244

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, delayed-

type 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 anti-

tumor 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

.

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.

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 anti-

tumoral, cytotoxic, anti-inflammatory and anti-

microbial 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, neutrophil-

mediated myeloperoxidase activity, and various

histopathological indicators. In addition, the extract

was effective at reducing inflammatory damage

induced by chronic 12-O-tetradecanoyl-phorbol-13-

acetate (TPA) exposure34

.

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


245

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

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 anti-

CD28 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 dose-

response 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 non-

specific 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


246

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 anti-

inflammatory 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 in-

vitro. In addition, the polysaccharide of G. glabra

dose-dependently improved immune and antioxidant

enzyme activities in mice. Glycyrrhizin (10) and β-

glycyrrhetinic 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 chromium-

induced 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 factor-

alpha (TNF-α) in peripheral blood mononuclear cells

(PBMCs). The increased expressions of p-I κB, NF-

κB 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


247

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 IL-

12 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 Abd-

Alla 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-glucopyranoside-

methylene-(8,8")-biapigenin (14), apigenin 7-O-β-D-

neohesperidoside (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

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


248

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 non-

cytotoxic 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 alloantigen-

induced 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 delayed-

type 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, anti-

inflammatory, 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 polysaccharide-

rich 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 TNF-

α, interleukin-1beta (IL-1β), IL-10, IL-12, interferon-

gamma (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 dose-

dependently 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


249

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 anti-

inflammatory 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 cell-

mediated 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 anti-

inflammatory, 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 non-

stressed 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 Co-

60 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

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 enzyme-

linked 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

.


250

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, antibody-

forming 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 PMA-

stimulated 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 sub-

Himalayan 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


251

chebula has been investigated for its effect on cell-

mediated 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 plaque-

forming 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, anti-

inflammatory, 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

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-O-

rutinoside (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


252

Structures of some important phytoconstituents


253

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,

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


254

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/01-

04/2010(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) 239-

246.

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 well-

known 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.


255

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, Anti-

wrinkle 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.

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

and function of natural killer cells in cervical cancer patients

with radiotherapy, J Med Assoc Thiland, 86 (2003) 61-68.

56 Hirazumi A & Furusawa E, An immunomodulatory

polysaccharide- rich substance from the fruit juice of

Morinda citrifolia (noni) with antitumour activity, Phytother

Res, 13 (1999) 380-387.

57 Mukherjee PK, Mukherjee D, Maji AK, Rai S & Heinrich M,

The sacred lotus (Nelumbo nucifera) - Phytochemical and

therapeutic profile, J Pharm Pharmacol, 61 (2009b) 407-

422.

58 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.

59 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.

60 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 co-

stimulatory molecules, Immunopharmacol

Immunotoxicolcol, 32 (2010b) 466–472.

61 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.

62 Salem ML, Immunomodulatory and therapeutic properties of

the Nigella sativa L. seed, Int Immunopharmacol 5 (2005)

1749-1770.

63 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.

64 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.

65 Sunila ES & Kuttan G, Immunomodulatory and antitumor

activity of Piper longum Linn. and piperine, J

Ethnopharmacol, 90 (2004) 339-346.

66 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.

67 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.

Immunomodulatory leads from medicinal plants

Documents

Transcript of Immunomodulatory leads from medicinal plants