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Original Article An Overview of Immunology - Systemic Review

P. Parveen1, P.Usha1, Ch.Sowjanya1, S.V.R.L.Sravika1, Bhavana Ragala1, and M. Gayatri Ramya2*

1Hindu College of Pharmacy Amaravathi Road, Guntur-522002 India. 2Acharya Nagarjuna University, University college of Pharmaceutical Sciences, Nagarjuna Nagar, Guntur-522510 India.

ABSTRACT

Immunology is one of the most rapidly developing areas of medical

biotechnology research and has great promises with regard to the prevention and treatment of a wide range of disorders such as the inflammatory diseases. In addition, infectious diseases are now primarily considered immunological disorders, while neoplastic diseases and organ transplantation and several autoimmune diseases are involved in an immunosuppressive state. Immunomodulators are natural or synthetic substances that help regulate or normalize the Address for . Immunomodulators correct immune systems that are Correspondence out of balance. The benefits of immunomodulators stem from their ability to stimulate natural and adaptive defense mechanisms.A Acharya Nagarjuna number of disorders such as immunodeficiency state, autoimmune University, University disease, cancer and viral can be treated with College of immunostimulants . The immune system is a part of body to Pharmaceutical detect the pathogen by using a specific receptor to produce Sciences, Nagarjuna immediately response by the activation of immune components cells, Nagar, Guntur-522510 , chemokines and also release of inflammatory mediator. India. They modulate and potentiate the immune system. E-mail: rajuph111 @gmail.com Keywords: Immunomodulators, Immunosuppressive, Immunology.

INTRODUCTION The immune system is designed to processing of the by the phagocytic protect the host from invading pathogens cells such as , monocytes, or and to eliminate disease. The primary object related cells. There are two types of immune in the past has been to suppress immune response are occurs in the human body: system to permit allotransplantation. I) Innate immune response Activation of immune system by “non-self” II) Adaptive immune response antigen (alloantigen) or “self” antigen (auto a. Humoral immunity antigen) is generally believed to require b. Cellular immunity

American Journal of Phytomedicine and Clinical Therapeutics www.ajpct.org Ramya et al______ISSN 2321 – 2748

I) Innate immune response: The like the temperature and pH of the body innate immune response is the first line of provide inappropriate living conditions for defense mechanism against physical, foreign organisms. Once pathogens have biochemical and cellular components. successfully entered the body, they are II) Adaptive immune response: addressed by the innate and/or the acquired a) Humoral immunity - Antibody or adaptive immune system3. Both systems production – killing extracellular organisms. consist of a multitude of cells and molecules b) Cell mediated immunity – that interact in a complex manner to detect cytotoxic / killer T-cells – killing virus and and eliminate pathogens4. Detection and tumour cells. Cellular immunity is expressed elimination depend upon chemical bonding: as cytotoxicity towards target cells by surfaces of immune system cells are covered activation of cytotoxic or “killer” T-cells. with various receptors, some of which The action of the cytotoxic T-cell is also chemically bind to pathogens, while others inhibited by adrenocorticosteroids1. But the bind to other immune system cells or humoral arm of the immune response is molecules to enable the complex signaling responsible for the production of the system that mediates the immune response5. antibodies; this is carried out by cells derived from the marrow (β-cell). Immunomodulators6 These are biological or synthetic Immunity2 substances that can stimulate, suppress or This may be defined as the body’s modulate any aspect of the immune system ability to identify and resist large numbers including both adaptive and innate arms of of infectious and potentially harmful the immune system6. microorganisms, enabling the body to prevent or resist diseases and inhibit organ Classification of immunomodulators and tissue damage2. The immune system is Clinically, immunomodulators can not confined to any one part of the body. be classified into the following three Immune stem cells, formed in the bone categories: marrow, may remain in the bone marrow Immunoadjuvants are used to until maturation or migrate to different body enhance the efficacy of and sites for maturation. Subsequently, most therefore could be considered specific immune cells circulate throughout the body, immune . Immunoadjuvants hold exerting specific effects. The immune the promise of being the true modulators of system has two distinct but overlapping the immune response. It has been proposed mechanisms with which to fight invading that they be exploited as selectors between organisms, the antibody-mediated defense cellular and humoral helper T1 (Th1) and system (humoral immunity) and the cell- helper T2 cells (Th2), immunoprotective, mediated defense system (cellular immunodestructive, and reagenic immunity). [immunoglobulin E (IgE)] versus IgG type immune responsesdposing a real challenge Immune systems3,4,5 to designers. The basic architecture of the immune Immunostimulants7 are inherently system is multilayered, with defenses on non-specific as they are envisaged as several levels. Most obvious and primary is enhancements to a body’s resistance to the skin: the first barrier against infection. infection. They can act through innate as Another is physiological, where conditions well as adaptive immune responses. In

AJPCT[1][8][2013]628-644 Ramya et al______ISSN 2321 – 2748 healthy individuals, the immunostimulants ultimately decreased fibrosis9. are expected to serve as prophylactic and can also reduce expression promoter agents, i.e., as of proinflammatory cytokines such as COX- immunopotentiators, by enhancing the basic 2 and NOS2. The influence of stressful level of immune response7. In the individual conditions on immune defense mechanisms with impairment of immune response, they is well documented as is the contribution of are expected to act as immunotherapeutic the HPA axis to the stress response. Stresses agents. such as injury, infection and disease result in Immunosuppressants3 are a the increased production of cytokines a structurally and functionally heterogeneous network of signalling molecules that group of drugs, which are often integrate actions of macrophages concomitantly administered in combination /monocytes, T lymphocytes and B regimens to treat various types of organ lymphocytes in mounting immune transplant rejection and autoimmune responses10. Among these cytokines diseases. (IL)-1, IL-6, and -a (TNF-a) stimulate the HPA axis Drugs used for Immunomodulation8 with IL-1 having the broadest range of All drugs which modify immune actions. IL-1 stimulates the release of CRH response generally categorized as by hypothalamic neurons, interacts directly immunomodulators. These can either with the pituitary to increase the release of function as: ACTH and may directly stimulate the 1. Immunosuppressants adrenal gland to produce glucocorticoids. 2. Immunostimulants. Factors that are inhibited include Some of these can have both the components of the network, properties depending on which component including -g (IFN-g), granulocy- of immune response they affect. There is temacrophage colony-stimulating factor also an upcoming generation of (GM-CSF), (IL-1, IL- 2, IL-3, immunosuppressants called tolerogens. IL-6, IL-8, and IL-12), and TNF-a.

1. Immunosuppressant drugs8

I. Inhibitors of Lymphocyte Gene Expression to Reduce Inflammatory Response Glucocorticoids:

Mechanism of Action9,10 Multiple mechanisms are involved in the suppression of inflammation by glucocorticoids. Glucocorticoids inhibit the production by multiple cells of factors that are critical in generating the inflammatory response. As a result there is decreased Therapeutic Uses release of vasoactive and chemoattractive Acute transplant rejection, graft- factors diminished secretion of lipolytic and versus-host disease in bonemarrow proteolytic enzymes decreased extravasation transplantation, rheumatoid and other of leukocytes to areas of injury and arthritides, systemic , systemic dermatomyositis, and

AJPCT[1][8][2013]628-644 Ramya et al______ISSN 2321 – 2748 other skin conditions, asthma and other with the cyclosporine/cyclophilin complex. allergic disorders, inflammatory bowel This prevents NFAT dephosphorylation disease, inflammatory ophthalmic diseases. such that NFAT does not enter the nucleus gene transcription is not activated and the T Adverse Effects lymphocyte fails to respond to specific Growth retardation in children, antigenic stimulation. Cyclosporine also avascular necrosis of bone, osteopenia, increases expression of transforming growth increased risk of infection, poor wound factor-b (TGF-b), a potent inhibitor of IL-2- healing, cataracts, hyperglycemia, and stimulated T-cell proliferation and hypertension11. generation of cytotoxic T lymphocytes (CTL). II. Inhibitors of Lymphocyte Signaling to Prevent Immune Cell Activation and Pharmacokinetics8 Proliferationa) Cyclosporine can be given orally or I.V. Its oral bioavailability is low (about Calcineurin Inhibitors 30%). Food decreases its absorption. It is metabolized by CYP3A which may result in Cyclosporine -drug interactions. Inactive metabolites Cyclosporine (cyclosporin A), a are excreted mainly in bile and then in feces cyclic polypeptide consisting of amino acids but minimally in urine. Plasma half life is is produced by the fungus species Beauveria about 24 hrs. nivea. Therapeutic Uses13 Mechanism of Action12 Kidney, liver, heart, and other organ Cyclosporine suppresses T-cell- transplantation, rheumatoid arthritis and dependent immune mechanisms such as psoriasis, early engraftment, extending kidney those underlying transplant rejection and graft survival, cardiac and liver some forms of autoimmunity. It transplantation, Behcet's acute ocular preferentially inhibits antigen-triggered syndrome, endogenous uveitis, atopic signal transduction in T lymphocytes, dermatitis13. blunting expression of many lymphokines including IL-2 and the expression of Adverse effects antiapoptotic proteins. Cyclosporine forms a Renal dysfunction, tremor, hirsutism, complex with cyclophilin, a cytoplasmic hypertension, hyperlipidemia, gum receptor protein present in target cells. This hyperplasia, hyperuricemia, hyper- complex binds to calcineurin, inhibiting cholesterolemia, nephrotoxicity, Ca2+-stimulated dephosphorylation of the hypertension, diabetogenic, Elevated LDL cytosolic component of nuclear factor for cholesterol. activated T-cells (NFAT)12. When cytoplasmic NFAT is dephosphorylated and Tacrolimus translocates to the nucleus and complexes Tacrolimus (PROGRAF, FK506) is a with nuclear components required for macrolide produced by complete T-cell activation including Streptomyces tsukubaensis. transactivation of IL-2 and other lymphokine genes. Calcineurin phosphatase activity is inhibited after physical interaction

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Mechanism of Action14 It binds to and inhibits a protein kinase Like cyclosporine, tacrolimus inhibits designated mammalian target of rapamycin Tcell activation by inhibiting calcineurin. (mTOR) which is a key enzyme in cell-cycle Tacrolimus binds to an intracellular protein progression. Inhibition of mTOR blocks cell- FK506-binding protein-12 (FKBP-12) an cycle progression at the G1 to S- phase immunophilin structurally related to transition. cyclophilin. A complex of tacrolimus-FKBP- 12, Ca2+, calmodulin, and calcineurin then Pharmacokinetics forms, and calcineurin phosphatase activity is Oral bioavailability is 15%. Fatty inhibited14. As described for cyclosporine the meal decreases its bioavailability. Protein inhibition of phosphatise activity prevents binding is 40-45% mainly with albumin. It is dephosphorylation and nuclear translocation extensively metabolized in liver by CYP3A4. of NFAT and inhibits T-cell activation. Sirolimus is excreted 91% in feces and only 2.5% in urine. Plasma half life is 62 hrs. Pharmacokinetics Tacrolimus can be given orally or I.V. Therapeutic Uses It is 99% metabolized in liver by CYP3A and Organ transplant inhibitor, graft has a plasma half life of 7-8 hrs. rejection, incorporated into stents to inhibit local cell proliferation and vessel Therapeutic Uses occlusion. Prophylaxis of solid-organ allograft rejection, kidney transplantation, pediatric Adverse Effects liver transplantation15. Dose-dependent increase in serum cholesterol and triglycerides, impaired renal Adverse effects function, prolong delayed graft function, Nephrotoxicity, neurotoxicity (tremor, Lymphocele, anemia, leukopenia . headache, motor disturbances and seizures), GI complaints, hypertension, hyperkalemia, III. Cytotoxic Agents to Reduce Lymphocyte hyperglycemia, and diabetes . Proliferationa) Antimetabolites17 b) Mammalian Target of Rapamycin (mTOR) Azathioprine Inhibitors16 Azathioprine (IMURAN) is a purine . It is an imidazolyl derivative Sirolimus of 6-mercaptopurine. Sirolimus (rapamycin; RAPAMUNE) is a macrocyclic lactone produced by Mechanism of Action Streptomyces hygroscopicus Following exposure to nucleophiles . such as glutathione, azathioprine is cleaved to Mechanism of Action8 6-mercaptopurine, which in turn is converted Sirolimus inhibits T-lymphocyte to additional metabolites that inhibit de novo activation and proliferation downstream of purine synthesis. 6-Thio-IMP, a fraudulent the IL-2 and other T-cell growth factor nucleotide, is converted to 6-thio-GMP and receptors. Sirolimus requires formation of a finally to 6-thio-GTP, which is incorporated complex with an immunophilin in this case into DNA17. Cell proliferation is thereby FKBP-12. However, the sirolimus-FKBP-12 inhibited impairing a variety of lymphocyte complex does not affect calcineurin activity. functions.

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Therapeutic Uses Adverse effects Allogeneic kidney transplantation, Leukopenia, diarrhoea, and vomiting, organ transplant rejection. sepsis associated with cytomegalovirus, in combination with mycophenolate mofetil has Adverse effects been associated with devastating viral Bone marrow suppression including including polyoma nephritis . leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon), b) Alkylating Agents8 increased susceptibility to infections (especially varicella and herpes simplex Cyclophosphamide viruses), hepatotoxicity, alopecia, GI toxicity, Cyclophosphamide is a unique pancreatitis. immunosuppressant as it suppresses B- lymphocyte proliferation but can enhance T- Mycophenolate Mofetil cell responses. Mycophenolate mofetil (CELLCEPT) is the 2-morpholinoethyl ester of Mechanism of Action mycophenolic acid (MPA). Alkylating agents introduce alkyl groups by forming covalent bonds with Mechanism of Action nucleophilic moieties such as phosphate, Mycophenolate mofetil is a prodrug sulfhydryl, hydroxyl, carboxyl, amino and that is rapidly hydrolyzed to the active drug, imidazole groups present in DNA or RNA. mycophenolic acid (MPA), a selective, By cross linking in between the strands of noncompetitive and reversible inhibitor of DNA they prevent the cell division and inosine monophosphate dehydrogenase protein synthesis. These drugs are most (IMPDH), an important enzyme in the de destructive to rapidly proliferating tissues and novo pathway of guanine nucleotide appear to cause cell death when they tend to synthesis. B and T lymphocytes are highly divide. The cytotoxicity of these drugs dependent on this pathway for cell correlates with the degree of DNA alkylation. proliferation while other cell types can use salvage pathways; MPA therefore selectively Therapeutic Uses inhibits lymphocyte proliferation and Autoimmune disorders (including functions including antibody formation, systemic lupus erythematosus), in patients cellularadhesion, and migration. with acquired factor XIII antibodies and bleeding syndromes, autoimmune hemolytic Pharmacokinetics anemia, antibody-induced pure red cell Mycophenolate mofetil undergoes aplasia, and Wegener's granulomatosis. rapid and complete to MPA after oral or intravenous administration. MPA, in Adverse effects turn is metabolized to the inactive phenolic Pancytopenia and hemorrhagic glucuronide MPAG. Most (87%) is excreted cystitis, graftversus- host disease syndrome, in the urine as MPA. nausea, vomiting, cardiac toxicity and electrolyte disturbances. Therapeutic Uses Prophylaxis of transplant rejection, renal transplantation.

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IV. Cytokine Inhibitors (Anticytokine- currently used in Cronh’s disease and Antibodies) rheumatoid arthritis. TNF-α and IL-1 are proinflammatory cytokines implicated in pathogenesis of Adalimumab8 rheumatoid arthritis and Crohn’s disease. Il-2 Is a human recombinant monoclonal binds to activated T- -lymphocytes and antibody to TNF-α. It is less antigenic than promotes their proliferation. Infliximab as it does not contain any foreign component. Its serum half life is 2 weeks. TNF-α Inhibitors18 Patients of rheumatoid arthritis may therefore Activated cytotoxic TH1 cells, administer single dose of 40 mg/0.8 ml macrophages and cells secrete TNF-α that to subcutaneously every 14 days 15. TNF receptors (TNFR1 or TNFR2) present on fibroblasts, neutrophils and vascular V. Antibodies Against Specific Immune Cell endothelial cells. Besides these, there are Moleculesa)8 soluble form of TNF-α receptor present in serum and synovial fluid. Activation of TNF- Polyclonal Antibodies α result in the release of cytokines IL-1, IL-6 and adhesion molecules that promote Antithymocyte Globulin (ATG) leukocyte activation and trafficking Antithymocyte globulin is a purified (migration). gamma globulin from the serum of rabbits immunized with human thymocytes. Etanercept18 Is genetically engineered fusion Mechanism of Action protein composed of two soluble TNFp75 Antithymocyte globulin contains receptors moieties linked to Fc portion of cytotoxic antibodies that bind to CD2, CD3, human IgG1. The drug serves as an CD4, CD8, CD11a, CD18, CD25, CD44, exogenously administered soluble TNF-α CD45, and HLA class I and II molecules on receptor and provides artificial binding sites the surface of human T lymphocytes. The to TNF-α. This prevents TNF-α from binding antibodies deplete circulating lymphocytes by to membrane bound TNFR1 and TNFR2. The direct cytotoxicity (both complement and drug is used primarily to treat rheumatoid cell-mediated) and block lymphocyte function arthritis, and psoriatic arthritis. by binding to cell surface molecules involved in the regulation of cell function. Infliximab8 Is a Chimeric monoclonal antibody Therapeutic Uses obtained by exposing the mice to human Acute renal transplant rejection, TNF- α. The antibody so produced is then recovery from ischemic reperfusion injury. fused to constant region IgG1 to decrease the antigenicity of the drug. The drug cross links Adverse effects with membrane bound TNF—α receptors on Fever and chills, hypotension, Serum cell surface to inhibit T-cell and sickness, glomerulonephritis, leukopenia and function and to prevent the release of other thrombocytopenia, increased risk of infection proinflammatory cytokines (IL-1, IL-6 and 8 and malignancy especially when multiple along with collagenase and immunosuppressive agents are combined metalloproteinases). Though it also has a 4,15,18,20. longer half life, it does not bind TNF-β. It

AJPCT[1][8][2013]628-644 Ramya et al______ISSN 2321 – 2748 a) Monoclonal Antibodies8,19 cardiorespiratory and CNS disorders, including aseptic meningitis. Potentially fatal Muromunab (Anti CD-3 Antibodies, OKT-3) severe pulmonary edema, acute respiratory Antibodies directed at the chain of distress syndrome, cardiovascular collapse, CD3, a trimeric molecule adjacent to the T- cardiac arrest. cell receptor on the surface of human T lymphocytes, have been used with VI. Inhibitors of Immune Cell Adhesion:8,20 considerable efficacy since the early 1980s in Efalizumab human transplantation. Efalizumab (LFA-1 Inhibitor) is a humanized IgG1 mAb targeting the CD11a Mechanism of Action chain of LFA 1 (lymphocyte function Muromonab-CD3 binds to the chain associated antigen). of CD3, a monomorphic component of the T- cell receptor complex involved in antigen Mechanism of action recognition, cell signaling and proliferation. Efalizumab binds to LFA-1 and Antibody treatment induces rapid prevents the LFA-1-ICAM (intercellular internalization of the T-cell receptor, thereby adhesion molecule) interaction to block T-cell preventing subsequent antigen recognition. adhesion, trafficking, and activation. Administration of the antibody is followed rapidly by depletion and extravasation of a Pharmacokinetics majority of T cells from the bloodstream and Pharmacokinetic and peripheral lymphoid organs such as lymph pharmacodynamic studies showed that nodes and spleen. This absence of detectable efalizumab produced saturation and 80% T cells from the usual lymphoid regions is modulation of CD11a within 24 hours of secondary both to cell death following therapy. complement activation and activation-induced cell death and to margination of T cells onto Therapeutic Uses vascular endothelial walls and redistribution Survival of murine skin and heart of T cells to nonlymphoid organs such as the allografts and monkey heart allografts, lungs. Muromonab-CD3 also reduces psoriasis, renal transplantation20. function of the remaining T cells, as defined by lack of IL-2 production and great VII. Miscellaneous-8 reduction in the production of multiple cytokines, perhaps with the exception of IL-4 Rho (D) Immune Globulin and IL 10. Rho (D) immune globulin is a concentrated (15%) solution of human IgG Therapeutic Uses containing a higher titer of antibodies against Acute organ transplant rejection. the Rho (D) antigen of the red cell.

Adverse effects Therapeutic uses Cytokine release syndrome, high Hemolytic disease of the newborn. fever, chills/rigor, headache, tremor, nausea/vomiting, diarrhea, abdominal pain, 2. Immunostimulants21 malaise, myalgias, arthralgias, and In contrast to immunosuppressive generalized weakness. Less common agents that inhibit the immune response in complaints include skin reactions and transplant rejection and autoimmunity, a few

AJPCT[1][8][2013]628-644 Ramya et al______ISSN 2321 – 2748 immunostimulatory drugs have been III. Thalidomide23 developed with applicability to infection, immunodeficiency, and cancer. These works Mechanism of action on cellular as well as humoral immune system Thalidomide has been reported to or both. decrease circulating TNF-α in patients with erythema nodosum leprosum, but to increase I. Bacillus Calmette-Guerin (BCG)8,22 it in patients who are HIV-seropositive. Live bacillus Calmette-Guerin (BCG; Alternatively, it has been suggested that the TICE BCG, THERACYS) is an attenuated, drug affects angiogenesis. live culture of the bacillus of Calmette and Guerin strain of Mycobacterium bovis. Therapeutic uses Severe, refractory rheumatoid Mechanism of action arthritis. Induction of a granulomatous reaction at the site of administration. Adverse effects Teratogenicity Therapeutic uses Treatment and prophylaxis of IV. Isoprinosine8 carcinoma of the urinary bladder, prophylaxis Isoprinosine (Inosiplex) is a complex of primary and recurrent stage Ta and/or T1 of the pacetamidobenzoate salt of N,N- papillary tumors after transurethral resection. dimethylamino-2- propanol: inosine in a 3:1 molar ratio. Adverse effects Hypersensitivity, shock, chills, fever, Mechanism of action malaise, and immune complex disease. Isoprinosine has been shown to augment production of cytokines such as IL- II. Levamisole8 1, IL-2 and IFN-γ. It increases proliferation of Levamisole (ERGAMISOL) was lymphocytes in response to mitogenic or synthesized originally as an but antigenic stimuli, increases active T-cell appears to restore depressed immune function rosettes and induces T-cell surface markers on of B lymphocytes, T lymphocytes, monocytes prothymocytes. and macrophages. Therapeutic uses Therapeutic uses Herpes simplex infections, subacute Adjuvant therapy with 5-fluorouracil sclerosing panencephalitis, acute viral after surgical resection in patients with encephalitis caused by herpes simplex, Duke’s stage C colon cancer, agranulocytosis. Epstein-Barr and measles viruses,

Adverse effects Adverse effects Flu-like symptoms, allergic Minor CNS , transient manifestation, nausea and muscle pain 4. nausea and rise of uric acid in serum and urine.

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Correlation of immunomodulators with , cardiotonic, , and other Ayurveda medicinal activities. Ayurveda is a most ancient and yet currently vital tradition practiced widely in of immunomodulatory India, Sri Lanka and other countries. It has a activities from putative medicinal plants24 sound philosophical and experimental basis. Mechanism of action of the Atharvaveda (around 1200 BC), Charak Rasayanas/ immunomodulators it has been Samhita and Sushrut Samhita (1000-500 BC) reported that the “Rasayanas” are are the main classic reference collections that rejuvenators, nutritional supplements and give a detailed description of over 700 herbs. possess strong antioxidant activities. They also exert antagonistic action on oxidative Concept of Rasayana3 stressors, giving rise to the formation of The word Rasayana, a combination of different free radicals. They are used mainly two words (rasa and ayana), refers to nutrition to combat the effects of ageing, and its transportation throughout the body. atherosclerosis, cancer, diabetes, rheumatoid Rasayana therapy enhances the qualities of arthritis, autoimmune disease and Parkinson’s rasa, enriching it with nutrients so one can disease. The Rasayana herbs seem to operate attain longevity, improved memory and through immunostimulant, immunoadjuvant, intelligence, freedom from disorder, and immunosuppressant activities or by youthfulness, excellence of hair, complexion affecting the effector arm of the immune and voice, optimum development of physique response.Mechanisms of immunomodulation and organs, mastery over phonetics and activity occur mainly via phagocytosis brilliance. As a dedicated stream of stimulation, macrophages activation, for immune promotion, immunostimulatory effect on peritoneal antidegenerative and rejuvenating health care, macrophages, lymphoid cells stimulation, the Rasayana therapy of Ayurveda is known cellular immune function enhancement and to prevent the effects of ageing and improve nonspecific cellular immune system effect, the quality of life for healthy as well as antigen-specific immunoglobulin production diseased individuals. Rasayana is helpful to increase, increased nonspecific immunity improve immunity and is normally advised mediators and natural killer cell numbers, during the degenerative phase of life, which reducing -induced leukopenia, starts from around 45 years in both males and and increasing circulating total white cell females. counts and interleukin-2 levels. Modulation of the immune responses through the stimulatory Plants as immunomodulators3 or suppressive activity of a phyto-extract may Several medicinal plants used in the help maintain a disease-free state in normal or Indian traditional system known as Rasayana unhealthy people. Agents that activate host (devoted to enhancement of the body’s defense mechanisms in the presence of an resistance) have attracted the attention of impaired immune response can provide scientists world-wide. As discussed below, supportive therapy to conventional several medicinal plants exhibit not only chemotherapy. Recently, three diosgenyl immunomodulatory activity but also a wide saponins isolated from Paris polyphylla have range of antioxidant, antiasthmatic, been reported to have immunostimulant antiarrhythmic, antiinflammatory, properties.Lymphocyte stimulation tests were hepatoprotective, hypocholesterolemic, performed on eight cycloartane-type saponins isolated from Astragalus melanophrurius, to

AJPCT[1][8][2013]628-644 Ramya et al______ISSN 2321 – 2748 determine the role of saponins in the of Zingiberaceae. India is a largest country immunomodulating effect of the plant. Higher which produces the curcuma longa linn concentrations of tested compounds have (about 90% of the total output of the world). exhibited inhibitory effects. Cycloartane and Curcuma is a genus of about 70 species if oleanane-type triterpenes from these species rhizomatous herbs distributed in south East have unmistakably induced interleukin-2 Asia especially India, China, Thailand and activity. Malaysia. The curcumin is used for the From the above review it should be treatment of anti-inflammatory, antiarthritic, evident that there are many medicinal plants common colds & coughs, jaundice agent. which exert immunomodulatory activity in Curcumin also inhibited the IL-2 induced experimental models at a particular dose. proliferation of splenic cells. The inhibition of Different types of screening methods both in IL-2 induced proliferation of cells was dose- vivo and in vitro have been employed to dependent; determine their pharmacological activity. Some medicinal plants may stimulate the Rhododendron spiciferum immune system, (e.g., Panax ginseng, The plant Rhododendron spiciferum Ocimum sanctum, Tinospora cordifolia, and belonging to the family Ericaceae. They will Terminalia arjuna), and some may suppress be widely used as a medicinal plant because the immune response (Alternanthera tenella). of their active constituent’s proanthocyanidin Also, various secondary metabolites (e.g., A-1 (PAA-1) is highly used for health. alkaloids, glycosides, saponins, flavonoids, Proanthocyanidin A-1 (PPA-1) is used as the coumarins, and sterols) exhibit a wide range free radical scavengers, anti-bacterial agents of immunomodulating activity. Thus a and effective enzyme inhibitors. They also successful review has been achieved by our exhibit the activity of vasodilators, anti- above survey. allergic, anti-inflammatory, cardio-protective, immune-stimulating, antiviral and estrogenic Immunomodulatory effects of some activities. traditional medicinal plants1 The Asteraceae family is the largest Caesalpinia bonducella flowering plants having immunomodulatory Caesalpinia bonducella belonging to activity. This family consists of about 900 the family Caesalpiniaceae. It is commonly genera and some 13,000 species. Different known as Nata Karanja. It is indigenous plant plants having immunomodulatory activity are. of India but also found to be Myanmar, Sri Lanka. The Caesalpinia prickly shrub, Boerhaavia diffussa globular shaped seeds with a smooth shining Boerhaavia diffusa, (Punarnava; surface. The Seeds of these plants consist of a Family Nyctaginaceae), is a creeping weed thick, brittle shell with a yellowish white found abundantly all over India. In Indian bitter fatty kernel. Caesalpini bonducella is traditional medicine, roots of this weed are used the shows following therapeutic activity used for the treatment of dyspepsia, jaundice, like antipyretic, antidiuretic, anthelmintic and enlargement of spleen, abdominal pain and as antibacterial, anti-anaphylactic and an antistres agent. antidiarrheal, antiviral, antiasthmatic, antiamoebic and anti-estrogenic. In the Curcuma longa treatment of liver disorder and tumor, Curcumin is a main active constituent Caesalpinia bonducella has been traditionally of curcuma longa linn belonging to the family used.

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Tinospora cordifolia CONCLUSION Tinospora cordifolia belonging to the family of Menispermaceae. This is a From this review it was concluded perennial climber distributed throughout the that immunology is probably one of the most tropical Indian subcontinent. It is categorized rapidly developing areas of medical as in Ayurveda and well known for its biotechnology research and has great adaptogenic and immunomodulatory activity promises with regard to the prevention and in fighting infection. The activity of this drug treatment of a wide range of disorders, the appears to be due to alkaloid. The drug shows inflammatory diseases of skin, gut, respiratory immunomodulatory activity. It is shown to be tract, and central organs. effective against various types of Immunomodulators are going to be a central experimental induce infection. part of medicine. Helping the body help itself by optimizing the immune system is of Nelumbo nucifera central importance in a society so stressed, Nelumbo nucifera is a plant belonging unhealthily nourished and exposed to toxins to the family of Nymphaeaceae. This plant is that most of us are likely to have a well-known aquatic medicinal plant which compromised immune systems. has used as a traditional medicine in India. Immunomodulation, however, is a The rhizome extract of Nelumbo nucifera, is normalizing process, which correct weak used the activity of hypoglycaemic, immune systems and temper immune systems , , diuretic, that are overactive, but they do not boost the antipyretic, psychopharmacological, anti- immune system. Immunomodulators are inflammatory. The seed of this plant is also becoming a viable adjunct to established used for the following activity including anti- modalities offering a novel approach for the treatment of infectious disease in the coming ischemic, antioxidant, hepatoprotective, st antiproliferative, , anti-inflammatory. The decades of 21 century. There are a number of plant contains betulinic acid and a steroidal natural agents (herbs) which are used for the pentacyclic triterpenoid .The each extract of enhancing of the body’s response to disease. this plant is used to the immunomodulatory In recent time a large number of drugs activity. extracted from the plants are coming in to the market by proper clinical trials. When taking Allium sativum any of these agents take proper advice on Allium sativum an important dose, length of treatment. medicinal plant having immunomodulatory effects. Three proteins showing REFERENCES immunomodulatory were separated from garlic by Q-Sepharose chromatography of 30 1. Singh Virendra Kumar*, Sharma Pramod kD ultrafiltrate of raw garlic extract. All these Kumar, Dudhe Rupesh, Kumar Nitin, Immunomodulatory effects of some proteins exhibit the mitogenic activity traditional medicinal plants J. Chem. Pharm. towards human peripheral blood Res., 2011, 3(1):675-684. lymphocytes, murine splenocytes and 2. Arshad hussain, Shadma wahab, Md. Parwez thymocytes Ahmad, A Systematic Review Of Herbal Immunomodulators In The Indian Traditional Health Care System Int.J.Inv.Pharm.Sci.,1(3)2013;261-266 3. Dinesh Kumar, Vikrant Arya, Ranjeet Kaur, Zulfiqar Ali Bhat,Vivek Kumar

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Table 1. Classification of Immunosuppressants

Sr. No. Mechanism of Action Examples 1. Inhibitors of Lymphocyte Gene Expression Glucocorticoids 2. Inhibitors of Lymphocyte Signaling a) Calcineurin Inhibitors Cyclosporine, Tacrolimus b) mTOR Inhibitors Sirolimus, Everolimus 3. Cytotoxic Agents a) Azathiprine, Methotrexate b) Alkylating agents 4. Cytokine Inhibitors a) TNF-α Inhibitors Etanercept, Infliximab b) IL-1 Inhibitors Anakinra c) IL-2 Inhibtors Daclizumab, Basiliximab 5. Antibodies Against Specific Immune Cell Molecules a) Polyclonal Antibodies Antithymocyte Globulin b) Monoclonal Antibodies Alemutuzmab 6. Inhibitors of Immune Cell Adhesion Efalizumab 7. Tolerogens or Inhibitors of Immune Cell Costimulation 8. Miscellaneous Immune Globulin

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Figure 1. Review for Immunomodulators in the Indian Traditional Health care system

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Figure 2. Mechanism of Action of cyclosporine

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Figure 3. Mechanism of action of sirolimus

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