INTRODUCTION:

Immunomodulators are biological response modifiers (BRM) that affect the immune response in either a positive or a negative fashion¹. The immune response requires the timely interplay of multiple cell types within specific micro environments to maintain immune homeostasis. The selectivity and flexibility that is necessary to regulate cell traffic under homeostatic and diseased conditions is provided by the differential distribution and regulated expression of cytokines and their receptors. As a consequence, cytokines are responsible for the development of phenotypes and are, therefore, logical targets for therapeutic immune modulation².

Immunodrugs include synthetic organics, biological, such as cytokines, antibodies, microbial and botanical natural products, which influence immunoregulatory cascades to bring about their specific stimulatory, suppressive or regulatory effect. Immune suppression has been widely studied for clinical applications³.

Historically, botanicals have been a mainstay of drug treatments and are currently receiving attention as sources of synergistic combinations. Here, recent developments in botanical immunodrugs discovery are reviewed.

Botanical immunodrugs

There are many herbal preparations alter immune function and display an array of immunomodulatory effects. In various in vitro and in vivo studies, herbal medicines have been reported to modulate cytokine secretion, histamine release, immunoglobulin secretion, class switching, cellular co-receptor expression, lymphocyte expression, phagocytosis⁴. A recent study, using a transgenic mouse model of melanoma, showed that the anticancer effects of popular Kampo medicine were mediated via an enhanced antigen-specific antitumour cytotoxic T-lymphocyte response⁵. Botanicals produce a diverse range of natural products with antimicrobial and immunomodulating potential, including isoflavonoids, indoles, phytosterols, polysaccharides, sesquiterpenes, alkaloids, glucans and tannins.There are many immune-related conditions with a high unmet clinical need and this is particularly true in the case of new viruses and the phenomenon of increasing antibiotic resistance. Botanical immune-modulating agents might be able to provide an alternative to costly immune therapeutic.

Natural product drug discovery

There are two major methods of bioprospecting natural products for investigation. First, the classical method that relies on phytochemical factors, serendipity and random screening approaches. Second, the use of traditional knowledge and practices as a drug discovery engine: this is also known as an ethno pharmacology approach, which is time and cost effective and could lead to better success than routine random screening^{6, 7}. Traditional methods, for example, Chinese Medicine, Japanese Kampo and Indian Ayurveda, are becoming important bioprospecting tools⁸. Ayurveda gives a separate class of immune-modulatory botanicals named Rasayana. Several botanicals from these texts have been studied for their immunomodulatory properties and have the potential to provide new scaffolds for safer, synergistic, cocktail immunodrugs⁹. In subsequent sections, examples are provided of important botanicals based on traditional knowledge that have been studied for the bioprospecting of potential immunodrugs. These botanicals have an array of compounds with diverse activities directed at various targets of the immune matrix, in cancer and in infection and inflammation.

Plant sterols¹⁰and sterolins are natural Immunomodulators found in some raw fruits and vegetables and in the alga, spirulina. Spreads and yoghurt-type foods containing high levels of plant sterols are commonly to be found on sale as ‘cholesterol-reducing’ agents. These compounds are destroyed when vegetables and fruits are cooked.

Recent research carried out in Russia has identified extracts of certain siberian plant species (Aconitum baikalense, Cirsium setosum and Saussurea controversy) as potent natural Immunomodulators. The extracts are dissimilar chemically but have similar immune system enhancing effects. They have successfully been used for the treatment of benign and malignant tumors, antibiotic-resistant infections, allergies, polyarthrites, thyroid diseases, Psoriasis¹¹ and other pathologies which can be treated with medicines only with difficulty. There are some true Immunomodulators. Some are manufactured and some occur in nature. It is always better to use the natural substances.

Colostrum¹² (also known colloquially as beestings or first milk) Colostrum is a form of milk produced by the mammary glands of mammals in late pregnancy. Most species will generate colostrum within one day of giving birth.

Human colostrums

Newborns have very small digestive system, and colostrum delivers its nutrients in a very concentrated low-volume form. It has a mild laxatives effect, encouraging the passing of the baby's first stool, which is called meconium. This clears excess bilurubin, a waste product of dead red blood cells, which is produced in large quantities at birth due to blood volume reduction, from the infant's body and helps prevent jaundice. Colostrum is known to contain antibodies called immunoglobulines such as IgA, IgG, and IgM in mammals. IgA is absorbed through the intestinal epithelium, travels through the blood, and is secreted onto other Type 1 mucosal surfaces. These are the major components of the adaptive immune system. Other immune components of colostrum include the major components of the innate immune system.

Colostrum is very rich in proteins, vitamin A, and sodium chloride, but contains lower amounts of carbohydrates, lipids, and potassium than normal milk. The most pertinent bioactive components in colostrum are growth factors and antimicrobial factors. The antibodies in colostrum provide passive immunity, while growth factors stimulate the development of the gut. They are passed to the neonate and provide the first protection against pathogens. The passive immunity from the mother gets transferred to the newborn¹³.

In animal husbandry

Livestock breeders commonly bank colostrum from their animals. Colostrum produced on a breeder's own premises is considered to be superior to colostrum from other sources, because it is produced by animals already exposed to (and thus making antibodies to) pathogens occurring on the premises. A German study reported that multiparous mares produced on average a liter (quart) of colostrum containing 70 grams of IgG¹⁴. Bovine colostrum is produced by cows for their new-born calves. In many dairy cows herds the calves are not permitted to nurse; rather, they are fed colostrum and later milk from a bottle then a bucket.

Human consumption of bovine colostrum

Assertions that colostrum consumption is of human benefit are questionable because most ingredients undergo digestion in the adult stomach, including antibodies and all other proteins. Bovine colostrum and its components are safe for human consumption, except in the context of intolerance or allergy to lactose or other components. It shows promise in the treatment or prevention of a variety of disease states^{15, 16, 17}.

Spirulina

Spirulina is a microscopic blue-green alga in the shape of a spiral coil, living both in sea and fresh water. Spirulina is the common name for human and animal food supplements produced primarily from two species of cyanobacteria: Arthospira platensis, and Arthrospira maxima.

Arthrospira is cultivated around the world, and is used as a human dietary supplement, as well as a whole food, and is available in tablet, flake, and powder form. It is also used as a feed supplement in the aqua culture, aquarium and poultry industries¹⁸.

Glycyrrhiza glabra

The root Glycyrrhiza glabra, commonly known as liquorice, has been used since ancient times in Indian, Chinese, Egyptian, Greek and Roman medicine. It is prominent in Ayurveda as Rasayana with cytoprotective and demulcent effects and is a popular home remedy for minor throat infections. Biologically active substances in liquorice roots include glycyrrhizic acid (GL) and its aglycone (GA), phenolic compounds, oligosaccharides and polysaccharides, lipids, sterine. Recently, GL and GA were shown to exert a hepatoprotective effect via modulation of immune-mediated hepatocyte toxicity, NF-κB and IL-10, which explains how their administration resulted in a down regulation of inflammation in the liver¹⁹. GL has been reported to increase the resistance to Candida albicans and herpes simplex virus-1 infection in animal models^{20, 21}. Many researchers have suggested that effects on the production of IFN and Th2 cytokines might be one of the mechanisms involved in the anti-infective process. Recently, glycyrrhizin was found to be active in inhibiting replication of the severe acute respiratory syndrome (SARS)-associated virus (FFM-1 and FFM-2). In the study, GA was found more effective compared with ribavirin, 6-azauridine, pyrazofurin or mycophenolic acid²². GL is also reported to have modulatory effects on the complement system. Reports indicate that GL blocks C5 or a more distal stage of the complement cascade, suggesting that it might have a role in preventing tissue injury not only in chronic hepatitis but also in autoimmune and inflammatory diseases²³.

Many researchers have reported response-modifying activity in flavonoids and chalcones isolated from the root extract. Modulation of the Bcl-2/Bax family of apoptotic regulatory factors, by components of the root, has been suggested as a possible mechanism for its reported cytoprotective activity²⁴. These activities include antioxidant, chemopreventive and antimicrobial activities²⁵. Chemical modification of GL and GA has been tried and significant improvement in anti-inflammatory, antiallergic, and antiulcer activities was observed²⁶. These observations indicate immune-modulating and biologial response modifier activities associated with GL²⁷.

Uncaria tomentosa

Uncaria tomentosa, also known as cat’s claw, is from the highlands of the Peruvian Amazon and has been used by natives for hundreds of years to treat immunologic and digestive disorders. It was found that two chemo types of this plant occur in nature, each with different alkaloid patterns²⁸ the roots of one type contain pentacyclic oxindoles and the other contains tetracyclic oxindoles, reported to have antagonistic activities. Tetracyclic oxindole alkaloids dose-dependently reduce the activity of pentacyclic oxindole alkaloids on human endothelial cells²⁹. Aqueous extracts and mixtures of oxindole alkaloids have shown positive influence on IL-1, IL-6 and IFN-γ production, suggesting immunoregulatory activity. In one clinical study, extract exhibited immune adjuvant activity with pneumococcal vaccine resulting in enhanced lymphocyte:neutrophil ratio and persistent antibody titre responses towards 12 pneumococcal serotypes³⁰.

In vitro, in vivo and gene expression studies on extracts of this plant indicated that anti-inflammatory activity is mediated through negation of NF-κB activation and suppression of TNF-α synthesis^{31, 32}. Randomized clinical studies on a purified extract, rich in pentacyclic alkaloids, demonstrated safer and moderate benefit in patients with active rheumatoid arthritis compared with those taking sulfasalazine or hydroxychloroquinine³³. Cytoprotection was observed in extracts devoid of alkaloids. The oxindole alkaloid-free fraction modulated apoptosis, tumour cell proliferation and DNA repair processes, leading to cytoprotection in chemically induced leucopoenia rat model³⁴. Extracts have also shown promising antitumour activity mediated via selective induction of apoptosis³⁵.

Echinacea spp.

The Echinacea plant is a member of the Compositae family; the three species of medicinal interest being Echinacea angustifolia, Echinacea purpurea and Echinacea pallida. Most uses of E. purpurea are based on its reported immunological properties. There are four types of constituents purported to be pharmacologically active molecules: phenolic caffeic acid derivatives, alkyl amides and isobutyl amides, polysaccharides and glycoprotein’s. Limited experimental evidence of immunostimulatory activity exists for caffeic acid derivatives and alkylamides³⁶. By contrast, Echinacea polysaccharides were found to directly activate non-specific immune cell types, such as monocytes, macrophages and natural killer (NK) cells³⁷. This characterization of Echinacea polysaccharides is the best demonstration of in vitro bioassay activity yielding reproducible in vivo pharmacological effects^{38, 39}. Several randomized trials have reported health benefits of Echinacea extracts in upper respiratory tract infections⁴⁰.

Withania somnifera

Withania somnifera (WS) –is also known as ashwagandha, Indian ginseng and winter cherry – is also classified as Rasayana in Ayurveda. The major biochemical constituents of WS root are steroidal alkaloids and steroidal lactones known as withanolides. Much of WS pharmacological activity has been attributed to withaferin A and withanolide D. WS is reported to have immunomodulatory, antitumour, cytoprotective and antioxidant properties⁴¹. All these activities are thought to be involved in the overall immunoregulatory properties of WS. Several preclinical studies have examined the cytoprotective potential of WS. In one study, WS exhibited myeloprotection in tumour model without compromising antitumour efficacy of cyclophosphamide, azathioprin or prednisolone⁴². In another instance, cytoprotection against experimental skin cancer was observed, where reduced levels of glutathione, superoxide dismutase, catalase and glutathione peroxidase returned to normal following WS administration ⁴³. WS exhibited modulatory effects on cytotoxic lymphocyte production leading to reduced tumour growth. Withaferin A was found to be better than doxorubicin in inhibiting growth of breast and colon cancer cell lines⁴⁴.

A recent study suggested that the increased production of inducible nitric oxide synthase was one of the possible mechanisms for the increased cytotoxic effect of macrophages exposed to WS extracts. Moreover, withaferin A in combination with radiotherapy increased the response to radio-resistant tumours⁴⁵. WS treatment in normal and tumour-bearing mice showed a positive influence on NK cell activity resulting in enhanced cell killing⁴⁶. Many studies, including our own, have demonstrated the immunomodulatory potential of WS, resulting in increased haemolytic titres, inhibition of delayed type sensitivities and an increase in phagocytic activity of macrophages^{47, 48}. We also observed that animals receiving WS showed immunoprotection to Bordetella pertussis infection, as evident by increased antibody titres and higher survival percentage⁴⁹. In a recent study, Immun-21, a polyherbal formulation containing WS, exhibited immunomodulatory activity leading to modest clinical benefits in groups of HIV patients⁵⁰. These observations suggest that WS could be used as an immunological adjuvant with multiple therapeutic benefits in cancer, infection and AIDS. In a comparative pharmacological investigation of WS and ginseng, the WS-treated group showed better anabolic and antistress activity than ginseng with additional anti-inflammatory activity⁵¹. WS has also been reported to be effective on acute-phase reactants, nitric oxide synthase and glycosaminoglycan synthesis in addition to immunoregulation⁵². Clinical studies on WS have shown moderate analgesic, anti-inflammatory and disease-modifying activity in arthritis patients^{53, 54}.

Tinospora cordifolia

Another Ayurvedic Rasayana known for immunomodulatory and cytoprotective activities is Tinospora cordifolia (TC), the chemistry of which has been studied extensively and its chemical constituents can be broadly divided into alkaloids, diterpenoids, steroids, flavonoids and lignans. Reviews have appeared on quaternary alkaloids and biotherapeutic diterpene glucosides of TC: syringin, cordiol, cordioside and coriofolioside were found to possess immunopotentiating activity⁵⁵. Much of the work has been conducted on berberine, jatrorrhizine, tinosporaside and columbin. The possible mechanism of immunomodulatory activity was elucidated as activation of macrophages, leading to increases in granulocyte– macrophage colony-stimulating factor (GM-CSF), leading to leukocytosis and improved neutrophil function. TC is also reported to inhibit C3-convertase of the classical complement pathway⁵⁶. In a recent study, a polysaccharide (α-D-glucan) derived from TC resulted in activation of NK cells, complement system, Th1-pathway cytokines, coupled with low nitric oxide synthesis⁵⁷. Antitumour activity of TC was evaluated in cultured HeLa cells and revealed that the effect of extract was comparable and better than doxorubicin treatment. Hepatoprotective activity of TC against carbon tetrachloride-induced liver damage has also been reported⁵⁸.

Vitamin D

Vitamin D is a steroid with a broken ring and, as such, is named a seco-steroid. Vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol) are the two major forms of vitamin D. Vitamin D₂ is derived from plants while vitamin D₃ is produced photo chemically in the animal epidermis. The action of UV radiation (295-310 nm) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylation’s (performed by the P₄₅₀ enzymes 25-hydroxylase and 1a-hydroxylase, respectively), gives rise to the active 1, 25-(OH) 2D. Vitamin D is produced after 15 min of sun exposure, at least twice a week. When exposed to UV rays during a longer period, the body degrades pre-vitamin D as fast as it generates it and equilibrium is achieved.

Vitamin D and the immune system

It has been known for more than 20 years that vitamin D exerts marked effects on immune cells ^{59, 60}. However, this non-classical action of vitamin D has recently gained a renewed attention since it has been shown that diminished vitamin D (i) induces immune-mediated symptoms in animal models of autoimmune diseases such as rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases⁶¹ and (ii) is a risk factor for viral infections, including tuberculosis⁶² and possibly influenza⁶³. It has also been demonstrated that vitamin D reverses age related Inflammatory changes in the rat hippocampus⁶⁴. Cells of the immune system patrolling the CNS might represent potential targets for vitamin D in immune or inflammatory diseases of the brain, but microglial cells and astrocytes Also respond to the hormone during EAE or brain inflammation^{65, 66, 67}.

Macromycetes fungi

Macro fungi are distinguished as important natural resources of immunomodulating and anticancer agents and with regard to the increase in diseases involving immune dysfunction, cancer, autoimmune conditions in recent years, applying such immunomodulator agents especially with the natural original is vital. These compounds belong mainly to polysaccharides especially β-D-glucan derivates, glycopeptides/protein complexes (polysaccharide-peptide/protein complexes), proteoglycans, proteins and triterpenoids. They are C-heterotrophic and obtain the essential nutrients through breaking down organic substances and absorbing them. The fungal body (thallus) is either a single cell or a thread like structure (hypha). A large number of branching hypha together constitutes the mycelium which gives raise to usually multiform spore-producing cells. In most types of fungi, spore-producing cells (basidia, asci, conidiophores) form a part of special structure made up hyphal tissue and called the fruit body (sporocarp). Although the fruit bodies are given to extraordinary variations in shape, size and coloring, these do remain fairly constant in individual fungus groups. The “mushroom” is a popular term that applied for the fungus has observable fruit body with the naked eye. Nowadays, fungi kingdom includes main five phyla including Chytridiomycota, Zygomycota, Glomeromycota, Ascomycota and Basidiomycota. The mushrooms are also called “Macromycetes” (a Latin name) in opposite the term “Micromycetes” (a Latin name for the fungi that are invisible with the naked eye) ⁶⁸. Compounds isolated from macro fungi that are known as immunomodulators that almost related to polysaccharides and their peptide or protein derivates. Also in some cases triterpenoids have closed to immunomodulating activity. These compounds are also worthwhile anti-infective and antitumor agents. A wide range of antitumor activity is proven for these fungi. Numerous reports have documented the ability of these compounds especially β-D-glucan derivates to nonspecifically activate cellular and humoral components of the host immune system so that they increase functional activity of macrophages, mononuclear cells, and neutrophils^{69, 70, 71}. Although the body's defense against microbial attack and against spontaneously arising malignant tumor cells comprises a dynamic orchestrated interplay of innate and acquired immune responses. Innate immunity (having macrophages, neutrophils, NK and DCs as gatekeepers), is regulated by chemical-messengers or cytokines and by activation of inflammatory and acute phase responses⁷².

Emblica offıcinalis

Fruits of Emblica offıcinalis (Family Euphorbiaceae) commonly known as “amla” or the Indian gooseberry, member of a small genus Emblica, are claimed to have anti-fungal, anti-bacterial, anti-diabetic, anti-clastogenic and hepatoprotective properties^{73, 74}. Besides having significant anti-oxidant⁷⁵, adaptogenic⁷⁶and anti-tumor activities⁷⁷. Amla fruit has also been demonstrated to possess cytoprotective properties in acute cadmium toxicity⁷⁸. Recent in vitro studies have also demonstrated that fruit extract of amla is able to relieve the Immunosuppressive effects of chromium in rat lymphocytes⁷⁹.

Evolvulus alsinoides

Shankhpushpi, Evolvulus alsinoides (family Convolvulaceae) has been extensively used in Ayurvedic practices as an alternative, antiphlogistic, febrifuge and as a brain tonic⁸⁰ to treat nervous debility and scrofula⁸¹. The juice of shankhpushpi has also been found to promote the healing of ulcers⁸².

CONCLUSION:

Immunoenhancers plays a big role in treatment of patients and to cure many diseases. People are also aware in consuming natural products that provide them nutrition’s. But most of them unknown what to eat for better results. Because some immune enhancers are not present in their diet. They are don’t know medically effect of food they are eating. Now it is like that multiple immune-modulating strategies will be necessary to achieve clinical success owing to complex interplay between pathways. We need designer drugs, which involve safer, curative and synergistic combinations. Bioprospecting will have a major role in identifying such combinations. The botanical immunodrugs discussed here have such potential because they offer additional therapeutic benefits to address associated conditions such as infection, inflammation and cancer. Botanical extracts provide cytoprotective, anticancer, anti-inflammatory and anti-infective activities in addition to immunoregulatory activity. For example, crude extract of Tinospora cordifolia has immunostimulant, anticancer and cytoprotective activities, where cytoprotective activities are attributed to polysaccharides and immunostimulant activity is attributed to diterpenoids⁸³. Recently, researchers observed antimicrobial activity coupled with immune modulation⁸⁴. Botanical immunodrugs could provide a unique opportunity to bioprospect diverse and synergistic chemicals moieties, which in combination might act on multiple targets and improve the therapeutic spectrum. Traditional knowledge and practices bring experiential wisdom to provide a safer and more cost effective platform for newer immunodrugs discovery.

REFERENCE:

1. Hausen B, Morris RE. Review of immunosuppression for lung transplantation:Novel drugs, new uses for conventional immunosuppressants, and alternative strategies. Clin Chest Med. 18; 1997: 353-66.

2. Oberholzer A, et al. Cytokine signaling–regulation of the immune response in normal and critically ill states. Crit Care Med. 28; 2000: N3-N12.

3. Nelson RP. Ballow M. Immunomodulation and immunotherapy: drugs, cytokines, cytokine receptors, and antibodies. J Allergy Clin Immunol. 111; 2003: S720–S743.

4. Plaeger SF. et al. Clinical immunology and traditional herbal medicines. Clin Diagn Lab Immunol. 10; 2003: 337-338.

5. Dai Y. et al. T-cell-immunity-based inhibitory effects of orally administered herbal medicine juzen-taiho-to on the growth of primarily developed melanocytic tumors in RET-transgenic mice. J Invest Dermatol. 117; 2001: 694-701.

6. Patwardhan B. et al. Ayurveda and natural products drug discovery. Curr Sci. 86; 2004: 789-799.

7. Rollinger JM. et al. Combining ethnopharmacology and virtual screening for lead structure discovery: COX-inhibitors as application example. J Chem Inf Comput Sci. 44; 2004: 480-488.

8. Patwardhan B. et al. Ayurveda: the ‘designer’ medicine: a review of ethnopharmacology and bioprospecting research. Indian drugs. 37; 2000: 213-227.

9. Rege NN. et al. Adaptogenic properties of six rasayana herbs in ayurvedic medicine. Phytother Res 13; 1999: 275–291.

10. www.health-answers.co.uk/sitostanol.html

11. www.health-answers.co.uk/psoriasis.html

12. Gottstein M. et al. Colostrum is vital ingredient to keep newborn lambs alive. Irish Independent. 3^th March 2009.

13. Pakkanen R, Aalto J. Growth factors and antimicrobial factors of bovine colostrum. International Dairy Journal. 7; 1997: 285-297.

14. Venner M, Markus RG, Strutzberg-Minder K, Nogai K, Beyerbach M, Klug E. Evaluation of immunoglobulin G concentration in colostrum of mares by ELISA, Refractometry and Colostrometry. 121; 2008: 66-72.

15. Uruakpa F. et al. Colostrum and its benefits: a review. Nutrition Research. 22; 2002: 755.

16. Playford RJ, Floyd DN, Macdonald CE, Calnan DP, Adenekan RO, Johnson W, Goodlad RA, Marchbank T. Bovine colostrum is a health food supplement which prevents NSAID induced gut damage. Gut. 44 (5); 1999: 653-8.

17. Carver JD, Barness LA. Trophic factors for the gastrointestinal tract. Clin Perinatol. 23 (2); 1996: 265-285.

18. Vonshak A. et al. Spirulina platensis (Arthrospira): Physiology, Cell-biology and Biotechnology. Taylor and Francis, London, 1997.

19. Oshikawa M. et al. Effects of glycyrrhizin on immune-mediated cytotoxicity. J Gastroenterol Hepatol 12; 1997: 243-248.

20. Sekizawa T. et al. Glycyrrhizin increases survival of mice with herpes simplex encephalitis. Acta Virol. 45; 2001: 51-54.

21. Utsunomiya T. et al. Glycyrrhizin improves the resistance of MAIDS mice to opportunistic infection of Candida albicans through the modulation of MAIDS-associated type-2 T- cell responses. Clin Immunol. 95; 2000: 145-155.

22. Cinatl J. et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 361; 2003: 2045-2046.

23. Fujisawa Y. et al. Glycyrrhizin inhibits the lytic pathway of complement–possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis. Microbiol Immunol 44; 2000: 799-804.

24. Jo EH, et al. Modulations of the Bcl- 2/Bax family were involved in the chemopreventive effects of licorice root (Glycyrrhiza uralensis Fisch) in MCF-7 human breast cancer cell. J Agric Food Chem 52; 2004: 1715-1719.

25. Barfod L. et al. Chalcones from Chinese liquorice inhibit proliferation of T cells and production of cytokines. Int Immunopharmacol. 2; 2002: 545-555.

26. Baltina LA. et al. Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr Med Chem. 10; 2003: 155-171.

27. Abe M. et al. Glycyrrhizin enhances interleukin-10 production by liver dendritic cells in mice with hepatitis. J Gastroenterol. 38; 2003: 962-967.

28. Reinhard KH. et al. Uncaria tomentosa (Willd.) D.C.: cat’s claw. J Altern Complement Med. 5; 1999: 143-151.

29. Wurm M. et al. Pentacyclic oxindole alkaloids from uncaria tomentosa induce human endothelial cells to release a lymphocyteproliferation- regulating factor. Planta Med. 64; 1998: 701-704.

30. Winkler C. et al. In vitro effects of two extracts and two pure alkaloid preparations of Uncaria tomentosa on peripheral blood mononuclear cells. Planta Med. 70; 2004: 205-210.

31. Sandoval-Chacon M. et al. Antiinflammatory actions of cat’s claw: the role of NF-kappa B. Aliment Pharmacol Ther. 12; 1998: 1279-1289.

32. Sandoval M. et al. Cat’s claw inhibits TNF-production and scavenges free radicals: role in cytoprotection. Free Radic Biol Med. 29; 2000: 158-165.

33. Mur E. et al. Randomized double-blind trial of an extract from the pentacyclic alkaloidchemotype of Uncaria tomentosa for the treatment of rheumatoid arthritis. J Rheumatol. 29; 2002: 678-681.

34. Sheng Y. et al. Treatment of chemotherapy-induced leucopoenia in a rat model with aqueous extract from uncaria tomentosa. Phytomedicine. 7; 2000: 137-143.

35. Sheng, Y. et al. Induction of apoptosis and inhibition of proliferation in human tumor cells treated with extracts of uncaria tomentosa. Anticancer Res. 18; 1998: 3363-3368.

36. Stimpel, M. et al. Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant echinacea purpurea. Infect Immun. 46; 1984: 845-849.

37. Anonymous. et al. Echinacea monograph. Altern Med Rev. 6; 2001: 411-414.

38. Melchart D. et al. Results of five randomized studies on the immunomodulatory activity of preparations of Echinacea. J Altern Complement Med. 1; 1995: 145-160.

39. Sheng, Y. et al. Induction of apoptosis and inhibition of proliferation in human tumor cells treated with extracts of uncaria tomentosa. Anticancer Res. 18; 1998: 3363-3368.

40. Henneicke-von ZH. et al. Efficacy and safety of a fixed combination phytomedicine in the treatment of the common cold (acute viral respiratory tract infection): results of a randomised, double-blind, placebo-controlled, multicentric study. Curr Med Res Opin. 15; 1999: 214-227.

41. Mishra LC. et al. Scientific basis for the therapeutic use of withania somnifera (Ashwagandha): a review. Altern Med Rev. 5; 2000: 334-346.

42. Diwanay S. et al. Immunoprotection by botanical drugs in cancer chemotherapy. J Ethnopharmacol. 90; 2004: 49-55.

43. Prakash J. et al. withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in swiss albino mice. Nutr Cancer. 42; 2002: 91-97.

44. Jayaprakasam B. et al. Growth inhibition of human tumor cell lines by withanolides from withania somnifera leaves. Life Sci. 74; 2003: 125-132.

45. Iuvone T. et al. Induction of nitric oxide synthase expression by withania somnifera in macrophages. Life Sci. 72; 2003: 1617-1625.

46. Davis L, Kuttan G. Effect of withania somnifera on cell-mediated immune responses in mice. J Exp Clin Cancer Res. 21; 2003: 585-590.

47. Davis L, Kuttan G. Immunomodulatory activity of withania somnifera. J Ethnopharmacol. 71; 2000: 193-200.

48. Ziauddin M. et al. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol. 50; 1996: 69-76.

49. Gautam M. et al. Immune response modulation to DPT vaccine by aqueous extract of withania somnifera in experimental system. Int Immunopharmacol. 4; 2004: 841-849.

50. Singh S. et al. An Indian herbal immunomodulator: highly effective in the treatment of HIV/AIDS. Conference on AIDS Asia Pacific, 5-10 October 2001, Melbourne, Australia Abstract No. WPO-1254.

51. Grandhi A. et al. A comparative pharmacological investigation of Ashwagandha and Ginseng. J Ethnopharmacol. 44; 1994: 131-135.

52. Agarwal R. et al. Studies on immunoregulatory activity of withania somnifera (Ashwagandha) extracts in experimental immune inflammation. J Ethnopharmacol. 67; 1999: 27-35.

53. Kulkarni RR. et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, crossover study. J Ethnopharmacol. 33; 1991: 91-95.

54. Chopra A. et al. Randomized double blind trial of an Ayurvedic plant derived formulation for treatment of rheumatoid arthritis. J Rheumatol. 27; 1991: 365-372.

55. Kapil A, Sharma S. Immunopotentiating compounds from tinospora cordifolia. J Ethnopharmacol. 58; 1997: 89-95.

56. Thatte UM. et al. Tinospora cordifolia induces colony-stimulating activity in serum. J Postgrad Med. 40; 1994: 202-203.

57. Nair RPK. et al. Immune-stimulating properties of a novel polysaccharide from themedicinal plant tinospora cordifolia. Int Immunopharmacol. 4; 2004: 1645-1659.

58. Diwanay SS. et al. Cytoprotection and immunomodulation in cancer therapy. Curr Med Chem Anti-Canc Agents. 4; 2004: 479-490.

59. Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha, 25-dihydroxyvitamin D₃ suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest. 74; 1984: 657-661.

60. Rigby WF, Stacy T, Fanger MW. Inhibition of T-lymphocyte mitogenesis by 1, 25-dihydroxyvitamin D₃ (calcitriol). J Clin Invest. 74; 1984: 1451-1455.

61. Szodoray P, Nakken B, Gaal J, Jonsson R, Szegedi A, Zold E, Szegedi G, Brun JG, Gesztelyi R, Zeher M, Bodolay E. The complex role of vitamin D in autoimmune diseases. Scand J Immunol. 68; 2008: 261-269.

62. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 311; 2006: 1770-1773.

63. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 134; 2006: 1129-1140.

64. Moore ME, Piazza A, McCartney Y, Lynch MA, Evidence that vitamin D₃ reverses age-related inflammatory changes in the rat hippocampus. Biochem Soc Trans. 33; 2005: 573-577.

65. Garcion E, Nataf S, Berod A, Darcy F, Brachet P. 1,25- Dihydroxyvitamin D₃ inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis. Brain Res Mol Brain Res. 45; 1997: 255- 267.

66. Garcion E, Sindji L, Montero-Menei C, Andre C, Brachet P, Darcy F. Expression of inducible nitric oxide synthase during rat brain inflammation, regulation by 1, 25-dihydroxyvitamin D₃. Glia. 22; 1998: 282-294.

67. Nataf S, Garcion E, Darcy F, Chabannes D, Muller JY, Brachet P, 1,25 Dihydroxyvitamin D₃ exerts regional effects in the central nervous system during experimental allergic encephalomyelitis. J Neuropathol Exp Neurol. 55; 1996: 904-914.

68. Mohammad FM. et al. International Immunopharmacology. 7; 2007: 701-724.

69. Liang J, Melican D, Cafro L, Palace G, Fisette L. Enhanced clearance of a multiple antibiotic resistant staphylococcus aureus in rats treated with PGG-glucan is associated with increased leukocyte counts and increased neutrophil oxidative burst activity. Int J Immunopharmacol. 20; 1998: 595-614.

70. Wakshull E, Brunke-Reese D, Lindermuth J, Fisette L, Nathans RS. PGG-glucan, a soluble beta-(1, 3)-glucan, enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B-like factor in human PMN: evidence for a glycosphingolipid beta-(1, 3)-glucan receptor. Immunopharmacology. 41; 1999: 89-107.

71. Burgaleta C, Territo MC, Quan SG, Golde DW. Glucanactivated macrophages: functional characteristics and surface morphology. J Reticuloendothel Soc. 23; 1978: 195-204.

72. Chihara G. et al. Immunopharmacology of Lentinan, a polysaccharide isolated from Lentinus edodes: its applications as a host defense potentiator. Int J Orient Med. 17; 1992: 57-77.

73. Dhir H, Roy AK, Sharma A, Talukdar G. Modification of clastogenicity of lead and aluminium in mouse bone marrow cells by Phyllanthus emblica fruit extract. Mutation Res. 24; 1991: 305-312.

74. Jeena KJ, Joy KL, Kuttan R. Effect of Emblica offıcinalis, Phyllanthus amarus and picrorhiza kurroa on N-nitrosodiethylamine induced heptocarcinogenesis. Cancer Letters. 136; 1999: 11-16.

75. Bhattacharya A, Chatterjee A, Ghosal S, Bhattacharya SK. Antioxidant activity of active tannoid principles of emblica offıcinalis (Amla). Ind J Exp Biol. 37; 1999: 676-680.

76. Rege NN, Thatte UM, Dahanukar SA. Adaptogenic properties of six rasayana herbs used in ayurvedic medicine. Phytotherapy Res. 13; 1999: 275-291.

77. Jose JK, Kuttan G, Kutan R. Antitumor activity of Emblica offıcinalis. J Ethanopharmacol. 75; 2001: 65-69.

78. Khandelwal S, Shukla LJ, Shanker R. Modulation of acute Cadmium toxicity by Emblica offıcinalis fruit in rat. Ind J Exp Biol. 40; 2002: 564-570.

79. SaiRam M, Neetu D, Yogesh B, Anju B, Dipti P, Pauline T. Cyto-protective and immunomodulatory properties of Amla (Emblica offıcinalis) on lymphocytes: an in-vitro study. J Ethanopharmacol. 81; 2002: 5-10.

80. Nadkarni KM and Nadkarani AK. Indian materica medica, vol. 1. Bombay: Popular Prakashan; 1982. P. 531.

81. Bhatt DC, Mehta SR, Mitaliya KD. Ethanomedicinal plants of Shetrunjaya hill of Palitans Gujrat. Ethanobotany. 11; 1999: 22-25.

82. Asolkar LV, Kakkar KK, Chakre OJ. Second supplement to glossary of Indian medicinal plant with active principles. Part I 1965–85. New Delhi: NISCAIR; 1992.

83. Kapil A, Sharma S. Immunopotentiating compounds from Tinospora cordifolia. J Ethnopharmacol. 58; 1997: 89-95.

84. Tan BK, Vanitha J. Immunomodulatory and antimicrobial effects of some traditional Chinese medicinal herbs: a review. Curr Med Chem. 11; 2004: 1423-1430.

Received on 17.02.2011 Modified on 01.03.2011

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