IMMUNOMODULATORS

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An overview of immunomodulatory drugs

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IMMUNOMODULATORS:

IMMUNOMODULATORS 4/12/2013 1 PURVI H KAKRANI

The Immune Response - why and how ?:

The Immune Response - why and how ? Discriminate: Self / Non self Destroy: Infectious invaders Dysregulated self (cancers) Immunity: Innate, Natural Adaptive, Learned 4/12/2013 2 PURVI H KAKRANI

Who are involved ?:

Who are involved ? Innate Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils Adaptive: B and T lymphocytes B: antibodies T : helper, cytolytic, suppressor. 4/12/2013 3 PURVI H KAKRANI

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IMMUNE MODIFIERS:

IMMUNE MODIFIERS Immunosuppressants Immunostimulants ? Immune tolerance 4/12/2013 5 PURVI H KAKRANI

Immunosuppressants:

Immunosuppressants Glucocorticoids Calcineurin inhibitors Cyclosporine Tacrolimus Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil 4/12/2013 6 PURVI H KAKRANI

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Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody Muromonab Anti IL-2 receptor antibody – Daclizumab, basiliximab Anti TNF alpha – infliximab, etanercept 4/12/2013 7 PURVI H KAKRANI

Immunostimulants:

Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines Interferons Interleukin-2 4/12/2013 8 PURVI H KAKRANI

Immunosuppressants:

Immunosuppressants Organ transplantation Autoimmune diseases Life long use Infection, cancers Nephrotoxicity Diabetogenic Problem 4/12/2013 9 PURVI H KAKRANI

Glucocorticoids:

Glucocorticoids Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1, IL-6 Inhibition of T cell proliferation Neutrophils, Monocytes display poor chemotaxis Broad anti-inflammatory effects on multiple components of cellular immunity 4/12/2013 10 PURVI H KAKRANI

USES - Glucocorticoids:

USES - Glucocorticoids Transplant rejection GVH – BM transplantation Autoimmune diseases – RA, SLE, Hematological conditions Psoriasis Inflammatory Bowel Disease, Eye conditions 4/12/2013 11 PURVI H KAKRANI

Toxicity:

Toxicity Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension 4/12/2013 12 PURVI H KAKRANI

Calcineurin inhibitors:

Calcineurin inhibitors Cyclosporine Tacrolimus Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes 4/12/2013 13 PURVI H KAKRANI

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Cyclosporine:

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 4/12/2013 15 PURVI H KAKRANI

Toxicity : Cyclosporine:

Toxicity : Cyclosporine Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic 4/12/2013 16 PURVI H KAKRANI

Drug Interaction : Cyclosporine:

Drug Interaction : Cyclosporine CYP 3A4 Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice Inducers: Rifampicin, Phenytoin Additive nephrotoxicity: NSAIDs 4/12/2013 17 PURVI H KAKRANI

Tacrolimus:

Tacrolimus Inhibits T-cell activation by inhibiting calcineurin Use Prophylaxis of solid-organ allograft rejection 4/12/2013 18 PURVI H KAKRANI

Toxicity - Tacrolimus:

Toxicity - Tacrolimus Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections Drug interaction Synergistic nephrotoxicity with cyclosporine CYP3A4 4/12/2013 19 PURVI H KAKRANI

Antiproliferative and Antimetabolic drugs:

Antiproliferative and Antimetabolic drugs Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others: Methotrexate Cyclophosphamide Thalidomide Chlorambucil 4/12/2013 20 PURVI H KAKRANI

Sirolimus:

Sirolimus Inhibits T-cell activation and Proliferation Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR) 4/12/2013 21 PURVI H KAKRANI

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Sirolimus:

Sirolimus Uses Prophylaxis of organ transplant rejection along with other drugs Toxicity Increase in serum cholesterol, Triglycerides Anemia Thrombocytopenia Hypokalemia Fever GI effects Risk of infection, tumors Drug Interactions : CYP 3A4 4/12/2013 23 PURVI H KAKRANI

Everolimus:

Everolimus Shorter half life compared to sirolimus Shorter time taken to reach steady state Similar toxicity, drug interactions 4/12/2013 24 PURVI H KAKRANI

Azathioprine:

Azathioprine Purine antimetabolite Incorporation of false nucleotide 6 Thio-IMP 6Thio-GMP 6Thio-GTP Inhibition of cell proliferation Impairment of lymphocyte function Uses Prevention of organ transplant rejection Rheumatoid arthritis 4/12/2013 25 PURVI H KAKRANI

Toxicity - Azathioprine :

Toxicity - Azathioprine Bone marrow suppression- leukopenia, thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol 4/12/2013 26 PURVI H KAKRANI

Mycophenolate Mofetil:

Mycophenolate Mofetil Prodrug  Mycophenolic acid Inhibits IMPDH – enzyme in guanine synthesis T, B cells are highly dependent on this pathway for cell proliferation Selectively inhibits lymphocyte proliferation, function – Antibody formation, cellular adhesion, migration 4/12/2013 27 PURVI H KAKRANI

Uses - Mycophenolate Mofetil:

Uses - Mycophenolate Mofetil Prophylaxis of transplant rejection Combination: Glucocorticoids Calcineurin Inhibitors Toxicity GI, Hematological Diarrhea, Leucopenia Risk of Infection 4/12/2013 28 PURVI H KAKRANI

Drug Interaction:

Drug Interaction Decreased absorption when co-administered with antacids Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion 4/12/2013 29 PURVI H KAKRANI

FTY720:

FTY720 S1P-R agonist – sphingosine 1 receptor Reduce recirculation of lymphocytes from lymphatic system to blood and peripheral tissues “Lymphocyte homing” – periphery into lymph node Protects graft from T-cell-mediated attack Uses Combination immunosuppression therapy in prevention of acute graft rejection 4/12/2013 30 PURVI H KAKRANI

Toxicity:

Toxicity Lymphopenia Negative chronotropic effect S1P-receptor on human atrial myocytes 4/12/2013 31 PURVI H KAKRANI

Antibodies:

Antibodies Against lymphocyte cell-surface antigens Polyclonal / Monoclonal 4/12/2013 32 PURVI H KAKRANI

Antibodies:

Antibodies Antithymocyte Globulin Monoclonal antibodies Anti-CD3 Monoclonal antibody (Muromonab-CD3) Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab) Campath-1H (Alemtuzumab) Anti-TNF Agents Infliximab Etanercept Adalimumab LFA-1 Inhibitor ( lymphocyte function associated) Efalizumab 4/12/2013 33 PURVI H KAKRANI

Anti-thymocyte Globulin:

Anti-thymocyte Globulin Purified gamma globulin from serum of rabbits immunized with human thymocytes Cytotoxic to lymphocytes & block lymphocyte function Uses Induction of immunosuppression – transplantation Treatment of acute transplant rejection Toxicity Hypersensitivity Risk of infection, Malignancy 4/12/2013 34 PURVI H KAKRANI

Anti-CD3 Monoclonal Antibody:

Anti-CD3 Monoclonal Antibody Muromonab-CD3 Binds to CD3, a component of T-cell receptor complex involved in antigen recognition cell signaling & proliferation 4/12/2013 35 PURVI H KAKRANI

Muromonab-CD3:

Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition 4/12/2013 36 PURVI H KAKRANI

Uses:

Uses Treatment of acute organ transplant rejection Toxicity “Cytokine release syndrome” High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness Prevention: Steroids 4/12/2013 37 PURVI H KAKRANI

Anti-IL-2 Receptor Antibodies :

Anti-IL-2 Receptor Antibodies Daclizumab and Basiliximab Bind to IL-2 receptor on surface of activated T cells  Block IL-2 mediated T-cell activation Uses Prophylaxis of Acute organ rejection Toxicity Anaphylaxis, Opportunistic Infections 4/12/2013 38 PURVI H KAKRANI

Campath-1H (Alemtuzumab):

Campath-1H (Alemtuzumab) Targets CD52 – expressed on lymphocytes, monocytes, Macrophages Extensive lympholysis – Prolonged T & B cell depletion Uses Renal transplantation 4/12/2013 39 PURVI H KAKRANI

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Anti-TNF Agents:

Anti-TNF Agents TNF – Cytokine at site of inflammation Infliximab Etanercept Adalimumab 4/12/2013 41 PURVI H KAKRANI

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Infliximab:

Infliximab Uses Rheumatoid arthritis Chron’s disease – fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis Toxicity Infusion reaction – fever, urticaria, hypotension, dyspnoea Opportunistic infections – TB, RTI, UTI 4/12/2013 45 PURVI H KAKRANI

Etanercept:

Etanercept Fusion protein Ligand binding portion of Human TNF- α receptor fused to Fc portion of human IgG1 Uses Rheumatoid arthritis 4/12/2013 46 PURVI H KAKRANI

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moderate to severely active crohn’s disease:

moderate to severely active crohn’s disease Adalimumab Recombinant human anti-TNF mAb 4/12/2013 48 PURVI H KAKRANI

LFA-1 Inhibitor - Efalizumab:

LFA-1 Inhibitor - Efalizumab Monoclonal Ab Targeting Lymphocyte Function Associated Antigen Blocks T-cell Adhesion, Activation, Trafficking Uses Organ transplantation Psoriasis 4/12/2013 49 PURVI H KAKRANI

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation:

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation DRUG SITE OF ACTION Glucocorticoids Glucocorticoid response elements in DNA (regulate gene transcription) Muromonab- CD3T-cell receptor complex (blocks antigen recognition) Cyclosporine Calcineurin (inhibits phosphatase activity) Tacrolimus Calcineurin (inhibits phosphatase activity) Azathioprine Deoxyribonucleic acid (false nucleotide incorporation) Mycophenolate Mofetil Inosine monophosphate dehydrogenase (inhibits activity) Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated T-cell activation) Sirolimus Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity ) 4/12/2013 50 PURVI H KAKRANI

Immunostimulants:

Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines Interferons Interleukin-2 4/12/2013 51 PURVI H KAKRANI

Immunization:

Immunization Vaccines Immune Globulin Rho (D) Immune Globulin 4/12/2013 52 PURVI H KAKRANI

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Levamisole:

Levamisole Antihelminthic Restores depressed immune function of B, T cells, Monocytes, Macrophages Adjuvant therapy with 5FU in colon cancer Toxicity Agranulocytosis 4/12/2013 54 PURVI H KAKRANI

Thalidomide:

Thalidomide Birth defect Contraindicated in women with childbearing potential Enhanced T-cell production of cytokines – IL-2, IFN- γ NK cell-mediated cytotoxicity against tumor cells USE: Multiple myeloma 4/12/2013 55 PURVI H KAKRANI

Bacillus Calmette-Guerin:

Bacillus Calmette-Guerin Live, attenuated culture of BCG strain of Mycobacterium Bovis Carcinoma Bladder Adverse Effects Hypersensitivity Shock Chills 4/12/2013 56 PURVI H KAKRANI

Interferons:

Interferons Antiviral Immunomodulatory activity Bind to cell surface receptors – initiate intracellular events Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis 4/12/2013 57 PURVI H KAKRANI

Interferon alfa-2b:

Interferon alfa-2b Hairy cell leukemia Malignant melanoma Kaposi sarcoma Hepatitis B Adverse reactions Flu-like symptoms – fever, chills, headache CVS- hypotension, Arrhythmia CNS- depression, confusion 4/12/2013 58 PURVI H KAKRANI

Interleukin-2 (aldesleukin):

Interleukin-2 (aldesleukin) Proliferation of cellular immunity – Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN- γ Uses Metastatic renal cell carcinoma Melanoma Toxicity Cardiovascular: capillary leak syndrome, Hypotension 4/12/2013 59 PURVI H KAKRANI

Immunization:

Immunization Active – Stimulation with an Antigen Passive – Preformed antibody 4/12/2013 60 PURVI H KAKRANI

Active immunization:

Active immunization Vaccines Administration of antigen as a whole, killed organism, or a specific protein or peptide constituent of an organism Booster doses Anticancer vaccines – immunizing patients with APCs expressing tumor antigen. 4/12/2013 61 PURVI H KAKRANI

Immune Globulin:

Immune Globulin Indications Individual is deficient in antibodies – immunodeficiency Individual is exposed to an agent, inadequate time for active immunization Rabies Hepatitis B 4/12/2013 62 PURVI H KAKRANI

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Nonspecific immunoglobulins Antibody-deficiency disorders Specific immune globulins High titers of desired antibody Hepatitis B, Rabies, Tetanus 4/12/2013 63 PURVI H KAKRANI

Rho (D) Immune Globulin:

Rho (D) Immune Globulin Antibodies against Rh(D) antigen on the surface of RBC Rh-negative women may be sensitized to “Foreign” Rh antigen on fetal RBC Anti-RH Antibodies produced in mother can damage subsequent fetuses by lysing RBC’s Hemolytic disease of newborn 4/12/2013 64 PURVI H KAKRANI

Immune tolerance:

Immune tolerance Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness Still experimental 4/12/2013 65 PURVI H KAKRANI

Summary:

Summary Immunosuppresion Calcineurin inhibitors Glucocorticoids Antimetabolites Newer immunosuppresive agents Effective control of rejection Glucocorticoid withdrawal 4/12/2013 66 PURVI H KAKRANI

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