IMMUNOMODULATORS

PURVI H KAKRANI

5/3/2013

PURVI H KAKRANI

1

The Immune Response - why and how ?

Discriminate: Self / Non self Destroy:
 

Infectious invaders Dysregulated self (cancers) Innate, Natural Adaptive, Learned

Immunity:
 

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PURVI H KAKRANI

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Who are involved ?

Innate

  

Adaptive:


Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils

 

B and T lymphocytes B: antibodies T : helper, cytolytic, suppressor.

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IMMUNE MODIFIERS Immunosuppressants Immunostimulants ? Immune tolerance 5/3/2013 PURVI H KAKRANI 5 .

thalidomide and chlorambucil 5/3/2013 PURVI H KAKRANI 6 .Immunosuppressants   Glucocorticoids Calcineurin inhibitors   Cyclosporine Tacrolimus  Antiproliferative / antimetabolic agents      Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others – methotrexate. cyclophosphamide.

Antibodies

Antithymocyte globulin Anti CD3 monoclonal antibody

Muromonab Daclizumab, basiliximab

Anti IL-2 receptor antibody –

Anti TNF alpha – infliximab, etanercept

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Immunostimulants


 

Levamisole Thalidomide BCG Recombinant Cytokines
 

Interferons Interleukin-2

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Immunosuppressants

Organ transplantation Autoimmune diseases

Problem
Life long use Infection, cancers Nephrotoxicity Diabetogenic

   

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IL-6 Inhibition of T cell proliferation Neutrophils.Glucocorticoids       Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1. Monocytes display poor chemotaxis Broad anti-inflammatory effects on multiple components of cellular immunity PURVI H KAKRANI 10 5/3/2013 .

Hematological conditions Psoriasis Inflammatory Bowel Disease. Eye conditions 5/3/2013 PURVI H KAKRANI 11 .Glucocorticoids      Transplant rejection GVH – BM transplantation Autoimmune diseases – RA. SLE.USES .

Toxicity        Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension 5/3/2013 PURVI H KAKRANI 12 .

Calcineurin inhibitors   Cyclosporine Tacrolimus    Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes 5/3/2013 PURVI H KAKRANI 13 .

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uveitis  Psoriasis  Aplastic anemia  Skin Conditions. autoimmunity IV. IBD. Lichen planus. Pemphigus vulgaris. Heart  Rheumatoid arthritis. Liver.Atopic dermatitis. Oral Uses  Organ transplantation: Kidney. Pyoderma gangrenosum 5/3/2013 PURVI H KAKRANI 15 . Alopecia Areata.Cyclosporine   More effective against T-cell dependent immune mechanisms – transplant rejection.

Toxicity : Cyclosporine         Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic 5/3/2013 PURVI H KAKRANI 16 .

Grape juice Inducers: Rifampicin. HIV PI. Antibiotics.Drug Interaction : Cyclosporine  CYP 3A4   Inhibitors: CCB. Antifungals. Phenytoin  Additive nephrotoxicity: NSAIDs 5/3/2013 PURVI H KAKRANI 17 .

Tacrolimus   Inhibits T-cell activation by inhibiting calcineurin Use  Prophylaxis of solid-organ allograft rejection 5/3/2013 PURVI H KAKRANI 18 .

Tacrolimus        Nephrotoxicity Neurotoxicity-Tremor. infections Drug interaction   Synergistic nephrotoxicity with cyclosporine CYP3A4 PURVI H KAKRANI 19 5/3/2013 . motor disturbances.Toxicity . headache. seizures GI Complaints Hypertension Hyperglycemia Risk of tumors.

Antiproliferative and Antimetabolic drugs      Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others:     Methotrexate Cyclophosphamide Thalidomide Chlorambucil 5/3/2013 PURVI H KAKRANI 20 .

Sirolimus   Inhibits T-cell activation and Proliferation Complexes with an immunophilin. Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR) 5/3/2013 PURVI H KAKRANI 21 .

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Sirolimus Uses  Prophylaxis of organ transplant rejection along with other drugs Toxicity  Increase in serum cholesterol. tumors  5/3/2013 Drug Interactions: CYP 3A4 PURVI H KAKRANI 23 . Triglycerides  Anemia  Thrombocytopenia  Hypokalemia  Fever  GI effects  Risk of infection.

Everolimus    Shorter half life compared to sirolimus Shorter time taken to reach steady state Similar toxicity. drug interactions 5/3/2013 PURVI H KAKRANI 24 .

Azathioprine   Purine antimetabolite Incorporation of false nucleotide 6Thio-GMP 6Thio-GTP 6 Thio-IMP  Inhibition of cell proliferation  Impairment of lymphocyte function Uses  Prevention of organ transplant rejection  Rheumatoid arthritis 5/3/2013 PURVI H KAKRANI 25 .

anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol PURVI H KAKRANI 26  5/3/2013 .Azathioprine      Bone marrow suppressionleukopenia. thrombocytopenia.Toxicity .

cellular adhesion. migration PURVI H KAKRANI 27 5/3/2013 .Mycophenolate Mofetil     Prodrug  Mycophenolic acid Inhibits IMPDH – enzyme in guanine synthesis T. function – Antibody formation. B cells are highly dependent on this pathway for cell proliferation Selectively inhibits lymphocyte proliferation.

Leucopenia  5/3/2013 Risk of Infection PURVI H KAKRANI 28 .Mycophenolate Mofetil   Prophylaxis of transplant rejection Combination: Glucocorticoids Calcineurin Inhibitors Toxicity GI.Uses . Hematological    Diarrhea.

Gancyclovir compete with mycophenolate for tubular secretion 5/3/2013 PURVI H KAKRANI 29 .Drug Interaction   Decreased absorption when coadministered with antacids Acyclovir.

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 PURVI H KAKRANI 30 5/3/2013 .

Toxicity   Lymphopenia Negative chronotropic effect  S1P-receptor on human atrial myocytes 5/3/2013 PURVI H KAKRANI 31 .

Antibodies   Against lymphocyte cellsurface antigens Polyclonal / Monoclonal 5/3/2013 PURVI H KAKRANI 32 .

Basiliximab) Campath-1H (Alemtuzumab) Infliximab Etanercept Adalimumab Efalizumab PURVI H KAKRANI 33  Anti-TNF Agents     LFA-1 Inhibitor (lymphocyte function associated)  5/3/2013 .Antibodies   Antithymocyte Globulin Monoclonal antibodies    Anti-CD3 Monoclonal antibody (Muromonab-CD3) Anti-IL-2 Receptor antibody (Daclizumab.

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 5/3/2013 PURVI H KAKRANI 34 .

a component of T-cell receptor complex involved in   antigen recognition cell signaling & proliferation 5/3/2013 PURVI H KAKRANI 35 .Anti-CD3 Monoclonal Antibody   Muromonab-CD3 Binds to CD3.

Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition 5/3/2013 PURVI H KAKRANI 36 .

Tremor.Uses  Treatment of acute organ transplant rejection Toxicity “Cytokine release syndrome” High fever. arthralgia. Headache. myalgia. Chills. weakness Prevention: Steroids PURVI H KAKRANI 37    5/3/2013 .

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 PURVI H KAKRANI 38  5/3/2013 .

monocytes.Campath-1H (Alemtuzumab)   Targets CD52 – expressed on lymphocytes. Macrophages Extensive lympholysis – Prolonged T & B cell depletion Uses Renal transplantation  5/3/2013 PURVI H KAKRANI 39 .

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Anti-TNF Agents  TNF – Cytokine at site of inflammation Infliximab Etanercept Adalimumab    5/3/2013 PURVI H KAKRANI 41 .

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urticaria. UTI 5/3/2013 PURVI H KAKRANI 45 .Infliximab Uses  Rheumatoid arthritis  Chron’s disease – fistulae  Psoriasis  Psoriatic arthritis  Ankylosing spondylosis Toxicity  Infusion reaction – fever. hypotension. RTI. dyspnoea  Opportunistic infections – TB.

Etanercept   Fusion protein Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1 Uses Rheumatoid arthritis  5/3/2013 PURVI H KAKRANI 46 .

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Adalimumab Recombinant human anti-TNF mAb moderate to severely active crohn’s disease 5/3/2013 PURVI H KAKRANI 48 .

Activation. Trafficking Uses Organ transplantation Psoriasis PURVI H KAKRANI 49   5/3/2013 .LFA-1 Inhibitor .Efalizumab   Monoclonal Ab Targeting Lymphocyte Function Associated Antigen Blocks T-cell Adhesion.

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation DRUG         SITE OF ACTION Glucocorticoid response elements in DNA (regulate gene transcription) CD3T-cell receptor complex (blocks antigen recognition) Calcineurin (inhibits phosphatase activity) Calcineurin (inhibits phosphatase activity) Deoxyribonucleic acid (false nucleotide incorporation) Inosine monophosphate dehydrogenase (inhibits activity) IL-2 receptor (block IL-2-mediated T-cell activation) Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity) Glucocorticoids MuromonabCyclosporine Tacrolimus Azathioprine Mycophenolate Mofetil Daclizumab. Basiliximab Sirolimus 5/3/2013 PURVI H KAKRANI 50 .

Immunostimulants     Levamisole Thalidomide BCG Recombinant Cytokines   Interferons Interleukin-2 5/3/2013 PURVI H KAKRANI 51 .

Immunization    Vaccines Immune Globulin Rho (D) Immune Globulin 5/3/2013 PURVI H KAKRANI 52 .

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Macrophages Adjuvant therapy with 5FU in colon cancer  5/3/2013 Toxicity Agranulocytosis PURVI H KAKRANI 54 .Levamisole    Antihelminthic Restores depressed immune function of B. Monocytes. T cells.

IFN-γ NK cell-mediated cytotoxicity against tumor cells USE: Multiple myeloma PURVI H KAKRANI 55  5/3/2013 .Thalidomide     Birth defect Contraindicated in women with childbearing potential Enhanced T-cell production of cytokines – IL-2.

Bacillus Calmette-Guerin   Live. attenuated culture of BCG strain of Mycobacterium Bovis Carcinoma Bladder Adverse Effects    Hypersensitivity Shock Chills PURVI H KAKRANI 56 5/3/2013 .

Interferons    Antiviral Immunomodulatory activity Bind to cell surface receptors – initiate intracellular events     Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis 5/3/2013 PURVI H KAKRANI 57 .

depression. chills. Arrhythmia CNS. confusion PURVI H KAKRANI 58    5/3/2013 . headache CVS.hypotension.Interferon alfa-2b     Hairy cell leukemia Malignant melanoma Kaposi sarcoma Hepatitis B Adverse reactions Flu-like symptoms – fever.

Interleukin-2 (aldesleukin)  Proliferation of cellular immunity – Lymphocytosis. Hypotension PURVI H KAKRANI 59 5/3/2013 . IFN-γ     Uses Metastatic renal cell carcinoma Melanoma Toxicity Cardiovascular: capillary leak syndrome. IL-1. eosinophilia. release of multiple cytokines – TNF.

Immunization   Active – Stimulation with an Antigen Passive – Preformed antibody 5/3/2013 PURVI H KAKRANI 60 .

killed organism. or a specific protein or peptide constituent of an organism  Booster doses  Anticancer vaccines – immunizing patients with APCs expressing tumor antigen. 5/3/2013 PURVI H KAKRANI 61 .Active immunization Vaccines  Administration of antigen as a whole.

Immune Globulin Indications  Individual is deficient in antibodies – immunodeficiency  Individual is exposed to an agent. inadequate time for active immunization   Rabies Hepatitis B 5/3/2013 PURVI H KAKRANI 62 .

Rabies. Tetanus  Specific immune globulins   5/3/2013 PURVI H KAKRANI 63 . Nonspecific immunoglobulins  Antibody-deficiency disorders High titers of desired antibody Hepatitis B.

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 PURVI H KAKRANI 64 5/3/2013 .

active state of antigenic specific nonresponsiveness Still experimental 5/3/2013 PURVI H KAKRANI 65 .Immune tolerance   Induction and maintenance of immunologic tolerance .

Summary  Immunosuppresion    Calcineurin inhibitors Glucocorticoids Antimetabolites Effective control of rejection Glucocorticoid withdrawal  Newer immunosuppresive agents   5/3/2013 PURVI H KAKRANI 66 .

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