ABT 704

Ankita Gurao 1

IMMUNOMODULATORSAND THEIRAPPLICATIONSThe immune system is one of our most complex biological systems in thebody. The basic role of the immune system is to distinguish selffrom non-self. The immune responses of the human body against anynon-self are of two types: innate and adaptive. Both these responseshave two components each, viz. cellular and humoral. In the innate cellularimmunity there is involvement of monocytes macrophage system,while in innate humoral immunity there is activation ofcomponent system. On the other hand the cellular component ofacquired immunity consists of T-lymphocytes while the humoralcomponent of this immunity involves the role of B lymphocytes.Normally in innate and acquired immune responses act in concerted mannerto contain or eradicate infection.When exposed to specific antigens, B-lymphocytes differentiateinto antibody producing plasma cells in the bone marrow.Simultaneously, T cells, under the influence of thymic hormones,migrate to the thymus and on appropriate stimulus byantigen presenting cells (APC) acquire T-cell receptor (TCR) andget differentiated to helper T-cells (CD4+) and cytotoxic T-cells( CD8+). The CD4+ (TH cell) subtypes of T-cells differentiatefurther outside the thymus into several phenotypes: TH1, TH2and TH3 which are distinguished by the different cytokines(IL-2 and IFN-γ) they synthesize. TH1 T-cells produce cytokinesthat stimulate proliferation and differentiation of T-lymphocytes and NKcells. These cytokine play an important role in cell mediated immunity(CMI). TG2 T-cells release cytokine (IL-4, IL-5, IL-10 and IL-13) thatstimulate B-lymphocytes production for humoral immunity. TH3T-cells play an important role in resting phases of immune response andin the production of anti-inflammatory immunoglobin-A (IgA)antibodies that are important in secretory immunity .Immunomodulators are natural or synthetic substances that help regulatethe immune system. Immunomodulators has the ability to stimulate naturaland adaptive defense mechanisms, such as cytokines, which enables the bodyto help itself. There are two types of immunomodulators:A)Immunosuppressants are the agents which suppress the immune systemand are used for the control of pathological immune response in autoimmunedisease, graft rejection etc.

ABT 704

Ankita Gurao 2

B)Immunostimulants are the agents which are envisaged to enhance body'sresistance against infections; they enhance the basal levels of immuneresponse, and in individuals with impairment of immune response asimmunotherapeutic agent.A) Immunosuppressant drugs: The immunosuppressants can becategorised as follows:

ABT 704

Ankita Gurao 3

I. Inhibitors of Lymphocyte Gene Expression to ReduceInflammatory Response-e.g. Glucocorticoids:• Mechanism of Action:

• Therapeutic Uses:Acute transplant rejection, graft vs host disease in bonemarrowtransplantation, rheumatoid and other arthritis, systemic lupuserythematosus, systemic dermatomyositis, psoriasis and other skinconditions, asthma and other allergic disorders, inflammatorybowel disease, inflammatory ophthalmic diseases.II. Inhibitors of Lymphocyte Signaling to Prevent Immune CellActivation and Proliferation-Eg) Calcineurin InhibitorsCyclosporine: Cyclosporine (cyclosporin A), a

ABT 704

Ankita Gurao 4

cyclic polypeptide consisting of 11 amino acids is produced by thefungus species Beauveria nivea.• Mechanism of Action:

• Therapeutic Uses:Kidney, liver, heart, and other organ transplantation, rheumatoidarthritis and psoriasis, early engraftment, extending kidney graftsurvival, cardiac and liver transplantation, Behcet's acute ocularsyndrome, endogenous uveitis, atopic dermatitis.III. Cytotoxic Agents to Reduce Lymphocyte Proliferation-Antimetabolites like Azathioprine and alkylating agents likeCyclophosphamide.Cyclophosphamide is a unique immunosuppressant as it suppressesB-lymphocyte proliferation but can enhance T-cell responses.

ABT 704

Ankita Gurao 5

• Mechanism of Action: Alkylating agents introduce alkyl groups by formingcovalent bonds with nucleophilic moieties such as phosphate, sulfhydryl,hydroxyl, carboxyl, amino and imidazole groups present in DNAor RNA. By cross linking in between the strands of DNAthey prevent the cell division and protein synthesis. These drugs aremost destructive to rapidly proliferating tissues and appear tocause cell death when they tend to divide. The cytotoxicity of thesedrugs correlates with the degree of DNA alkylation.• Therapeutic Uses:Autoimmune disorders (including systemic lupus erythematosus), inpatients with acquired factor XIII antibodies and bleedingsyndromes, autoimmune hemolytic anemia, antibody-induced purered cell aplasia, and Wegener's granulomatosis.IV. Cytokine Inhibitors (Anticytokine-Antibodies)-a) TNF-α Inhibitors eg) Etanercept, Infliximab, Adalimumabb) IL-1 Inhibitors eg)Anakinrac) IL-2 Inhibtors eg)Daclizumab, Basiliximab• Mechanism of Action:TNF-α and IL-1 are proinflammatory cytokines implicated inpathogenesis of rheumatoid arthritis and Crohn’s disease.Il-2 binds to activated T- -lymphocytes and promotes their proliferation.• Therapeutic Uses:Etanercept is used primarily to treat rheumatoid arthritis, and psoriaticarthritis. IInfliximab is a Chimeric monoclonal antibody obtained by exposingthe mice to human TNF- α. . It currently used in Cronh’s disease andrheumatoid arthritis. Adalimumab is a human recombinant monoclonalantibody to TNF-α used in rheumatoid arthritisV. Antibodies Against Specific Immune Cell Molecules-a) Polyclonal Antibodies eg)Antithymocyte Globulin (ATG)b)Monoclonal Antibodies eg)Alemutuzmab,MuromunabAntithymocyte Globulin (ATG): Antithymocyte globulin is a purified gammaglobulinfrom the serum of rabbits immunized with human thymocytes.

ABT 704

Ankita Gurao 6

• Mechanism of Action:Anti thymocyte globulin contains cytotoxic antibodies that bindto CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and HLA class I andII molecules on the surface of human T lymphocytes. The antibodiesdeplete circulating lymphocytes by direct cytotoxicity and blocklymphocyte function by binding to cell surface moleculesinvolved in the regulation of cell function.• Therapeutic Uses:Acute renal transplant rejection, recovery from ischemic reperfusionInjury.VI. Inhibitors of Immune Cell Adhesion:Eg) Efalizumab (LFA-1 Inhibitor) is a humanized IgG1mAb targeting theCD11a chain of LFA-1 (lymphocyte function associated antigen).• Mechanism of action:Efalizumab binds to LFA-1 and prevents the LFA-1-ICAM(intercellular adhesion molecule) interaction to block T-celladhesion, trafficking, and activation.• Therapeutic uses:Hemolytic disease of the newborn.B) Immunostimulants:In contrast to immunosuppressive agents that inhibit theimmune response in transplant rejection and autoimmunity, afew immunostimulatory drugs have been developed with applicability toinfection, immunodeficiency, and cancer. These works on cellular as well ashumoral immune system or both.I. Bacillus Calmette-Guerin (BCG):Live bacillus Calmette-Guerin (BCG; TICE BCG, THERACYS) isan attenuated, live culture of the bacillus of Calmette and Guerin strainof Mycobacterium bovis.• Mechanism of action:Induction of a granulomatous reaction at the site of administration.

ABT 704

Ankita Gurao 7

• Therapeutic uses:Treatment and prophylaxis of carcinoma of the urinary bladder,prophylaxis of primary and recurrent stage Ta and/or T1 papillarytumors after transurethral resection.II. Levamisole:Levamisole (ERGAMISOL) was synthesized originally as ananthelmintic but appears to restore depressed immune function of Blymphocytes, T lymphocytes, monocytes and macrophages.• Therapeutic uses:Adjuvant therapy with 5-fluorouracil after surgical resection inpatients with Duke’s stage C colon cancer, agranulocytosis.III. Thalidomide:• Mechanism of action:Thalidomide has been reported to decrease circulating TNF-αin patients with erythema nodosum leprosum, but to increaseit in patients who are HIV-seropositive. Alternatively, it hasbeen suggested that the drug affects angiogenesis.• Therapeutic uses:Severe, refractory rheumatoid arthritis.IV. Isoprinosine:Isoprinosine (Inosiplex) is a complex of the pacetamidobenzoate saltof N,N-dimethylamino-2- propanol: inosine in a 3:1 molar ratio.• Mechanism of action:Isoprinosine has been shown to augment production ofcytokines such as IL-1, IL-2 and IFN-γ. It increases proliferationof lymphocytes in response to mitogenic or antigenic stimuli, increases activeT-cell rosettes and induces T-cell surface markers onprothymocytes.• Therapeutic uses:Herpes simplex infections, subacute sclerosing panencephalitis,acute viral encephalitis caused by herpes simplex, Epstein-Barr andmeasles viruses.

ABT 704

Ankita Gurao 8

V. Immunocynin:It is a stable form of haemocynin, a non-haeme, oxygencarrying, copper-containing protein found in arthropods and molluses.• Therapeutic uses:Urinary bladder cancer.VI. Recombinant Cytokines:Few important recombinant cytokines used as immunostimulants and theirexamples are as follows.