Immunomodulators

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Immunomodulators Dr. Ashish J PG Dept of Microbiology NMCH&RC

Definition:

Definition Immunomodulators can be defined ‘as any agents that augments or diminishes immune responses.’

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Who are involved ? Innate Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils Adaptive: B and T lymphocytes B: antibodies T : helper, cytolytic, suppressor.

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Regulation or stimulation of immune response divided into Compounds derived from bacteria Compounds derived from eukaryotes Biochemical compounds

Compounds derived from bacteria:

Compounds derived from bacteria Among first immunostimulators Complete freund’s adjuvant (CFA) BCG Certain mycobacterial heat shock protein Other bacterial substances like toxins of Staph aureus . OK 432ch

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CFA Useful in animals Boosts immune response Contains mycobacterial derivatives

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BCG vaccine Treat certain malignancies like malignant melanoma and urinary bladder carcinoma Stimulate macrophage T and B lymphocytes and NK cell function. Augment Interleukin-1 production

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OK 432 Prepared from culture medium after penicillin treatment of strain of group A streptococcus pyogenes. Augment macrophage and natural killer activity. Active against head, neck and gastrointestinal tumor and lung.

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Whole or Fractionated preparation of other organism show immunomodulator effect Lipopolysaccharide from gram negative bacteria also shows immunostimulatory

Compounds derived from Eukaryotes:

Compounds derived from Eukaryotes Thymic hormones Cytokines Cytokine antagonists Monoclonal antibodies

Thymic hormones :

Thymic hormones Thymosin Thymulin Thymopentin Thymo stimulation & Thymic humoral factor- Immunostimulatory actions Clinical benefits in many viral infection, such Hepatitis B Herpes zoster Herpes labialis Chronic Trichophyton rubrum

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Primary immjunodeficiencies Used as adjunct with Chemotherapy in small cell carcinoma of lung

Cytokines:

Cytokines Low molecular weight soluble proteins (polypeptides) produced in response to microbes and other antigens Exhibit autocrine , paracrine and endocrine effects Affect induction and intensity of cellular growth and differentiation, cell activation, tissue inflammation and tissue repair.

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Subdivided into Interferon Interleukin Colony stimulating factor Growth and differentiation factor

Interferon (IFN):

Interferon (IFN) Viral infection Neoplastic disease Pegylated interferon 3 types of IFN alpha IFN beta IFN gamma IFN

Alpha IFN:

Alpha IFN Produced by leukocytes Induced by virus infected cells - Prevent viral replication - Increase MHC-I expression on viral infected cells helping their recognition by CD 8 T-cells - Increase cytotoxic action of Nk cells - Inhibit cell proliferation and tumor growth

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Hairy cell leukemia- 90% respond but relapse Other condition are CML Multiple myeloma NHL Cutaneous T cell lymphoma Malignant melanoma Renal cell carcinoma Bladder and ovarian cancer AIDS related Kaposis sarcoma

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Many viral infection also Condyloma acunatum Laryngeal papillomatosis Herpetic keratoconjunctivitis Rhinovirus infection Hepatitis B and C

Gamma IFN:

Gamma IFN IFN- γ produced by NK cells,TH1 cells, CD8 T-cells Activate Macrophages - Increase expression of MHC-I and II on APCs - Enhance cytotoxic actions of Nk cells - Promote production of TH1 and inhibits proliferation of TH2

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Active against many tumors and viral infection. AIDS related Kaposi carcinoma. Used when resistance to IFN- alpha Also in Collagen vascular disease Lepromatous leprosy

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Side effects Acute malaise Flu like symptoms Chronic fatigue Anorexia Elevation of hepatitis enzyme Lipidemia Arthralgia Hypocalcimia Sever headache

Interleukins (IL):

Interleukins (IL) Wide range of action IL-2 - Treat Renal Cell Carcinoma & Malignant Melanoma. Due to activation of lymphokines and activated killer cells. Reverses CD4 T cell lymphopenia IL-4 - Promotes IgE production and mast cell stimulators. IL-4 antitumour activity

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TNF- Limited therapeutic potential because of toxicity IL-10- Cytokine with counter regulatory properties. Useful in treatment of autoimmune disease.

Colony stimulatory factor (CSF):

Colony stimulatory factor (CSF) 3 cytokines with CSF properties are being used routinely. 1. Erythropoietin- 2. Granulocyte CSF- Increase myeloid cell precursors 3. Granulocyte macrophage CSF- increased monocyte macrophage function

Growth and Differentiation factor:

Growth and Differentiation factor Transforming growth factor TGF – Secreted fromT cells, macrophages , Inhibits T-cell proliferation and effector functions, inhibits B- cell proliferation. Benefits in wound healing Anti-proliferative and anti- inflamatory effects in vitro Anti allergy drugs- inhibits IL-4 stimulated synthesis of IgE . Causes glomerulonephrosis and sclerosis.

Cytokine antagonists:

Cytokine antagonists Nos of protein that inhibit biological activity of cytokine. IL-1 receptor antagonist (RA). Bind to IL-1 but no activation. Anti- inflamatory activity in animmal model of many human disease Eg . Septic shock, IBD, ARDS, PAN(clinical trials)

Monoclonal Antibodies:

Monoclonal Antibodies Derived from a single B cell clone Same immunoglobulin class and allotype Got various uses Studies with murine anti TNF Mab have shown improvement in condition

Therapeutic uses:

Therapeutic uses 1. Magic bullet therapy- M Ab with cytotoxic drug combination used in neuroblastoma, thyroid Ca and Ovarian Ca. 2. Antitumor agents in specific carcinomas like Breast Ca and Hodgkin’s lymphoma. 3. Prevention of GVHD- MAb with complement or toxins like ricin / abrin 4. Anticytokine effect- TNF alpha, IL-1, IL-6, IL-15 ,, Alpha 4 Beta1, CD 25 5. Passive immunity in acute attack in Rabies, Tetanus, Rh incompatibility

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FDA APPROVED MONOCLONAL ANTIBODIES H 2003 Psoriasis Raptiva ™ Genentech/Xoma C 1997 Non-Hodgkin ’ s Lymphoma Rituxan ® BiogenIdec/Genentech/Roche M 2003 Non-Hodgkin ’ s Lymphoma Bexxar ® Corixa/GlaxoSmithKline C 2004 Colorectal Cancer Erbitux ™ BMS/ImClone Systems H 2003 Asthma Xolair ® Novartis/Genentech/Tanox PD 2002 Rheumatoid Arthritis Humira ™ Abbott/CAT H 2001 Chronic Lymphocytic Leukemia Campath ® Schering /ILEX Oncology H 2000 Acute Myleoid Leukemia Mylotarg ™ Wyeth C 1998 Acute Transplant Rejection Simulect ® Novartis C 1998 Crohn ’ s, Rheumatoid Arthritis Remicade ® J & J H H 1998 2004 Breast Cancer Colorectal Cancer Herceptin ® Avastin ® Genentech/Roche H 1998 Viral Respiratory Disease Synagis ® MedImmune/Abbott H 1997 Acute Transplant Rejection Zenapax ® PDLI M 2002 Non-Hodgkin ’ s Lymphoma Zevalin ™ BiogenIdec C 1994 Acute Cardiac Conditions ReoPro ® J&J/Eli Lilly M 1986 Organ Transplant Rejection Orthoclone-OKT ® Ortho Biotech Antibody Type (2) Date of FDA Approval Indications Name of Product (1) Company Name

Therapeutic uses:

Therapeutic uses 6. MAb to Ig-E in hypersensitivity - omalizumab in allergic asthma, rhinitis and crippling food allergies 7. Treatment of autoimmune diseases - NZB-NZW mice(lupus), NOD mice(lymphocytic infiltration, DM) - stage of the disease - animal model is not a perfect predictor of human response (RA, MS )

Biochemical agents:

Biochemical agents Potential immunomodulator AIDS. Invivo benefit?

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Some of the agents are Levamizole Pramobex Diethyl dithiocarbamate Azimexone Glucocorticoids

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Levamisole : Imidathiazole compound Antihelminthic Immunotrophic but mechanism of action not known. Treatment in Colon cancer. Toxicity- Agranulocytosis .

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Pramobex : Related to levamizole Delay progression of AIDS. Antibody to cytokine Diethyl dithiocarbamate Activity on HIV infection and cancers.

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Azimexone : Azinidine derivative. Stimulates delayed type hypersensitivity and inhibits Graft v host response. No antitumour activity. Glucocorticoids : Induce redistribution of lymphocytes. Down regulation of IL-1, IL-6 Inhibition of T cell proliferation Broad anti-inflammatory effects

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USES - Glucocorticoids Transplant rejection GVH – BM transplantation Autoimmune diseases – RA, SLE, Hematological conditions Psoriasis Inflammatory Bowel Disease, Eye conditions

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Cyclosporine More effective against T-cell dependent immune mechanisms – transplant rejection, autoimmunity IV, Oral Uses Organ transplantation: Kidney, Liver, Heart Rheumatoid arthritis, IBD, uveitis Psoriasis Aplastic anemia Skin Conditions- Atopic dermatitis, Alopecia Areata , Pemphigus vulgaris , Lichen planus , Pyoderma gangrenosum

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Tacrolimus Inhibits T-cell activation by inhibiting calcineurin Use Prophylaxis of solid-organ allograft rejection

References:

References Kuby textbook of immunology Lippincott textbook of immunology Roit textbook of immunology Ananthnarayan textbook of microbiology ‘ Immunomodulators ’ Drug discovery 2007 Abbas k and Murphy “ Functional features of helper T lymphocytes” 2006 Immunomodulators a review SS Singh 2006 PINSA

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