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PURVI H KAKRANI
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Immunity:
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Innate
Adaptive:
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IMMUNE MODIFIERS
Immunosuppressants
Immunostimulants
? Immune tolerance
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Immunosuppressants
Cyclosporine Tacrolimus
Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others methotrexate, cyclophosphamide, thalidomide and chlorambucil
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Antibodies
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Immunostimulants
Interferons Interleukin-2
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Immunosuppressants
Problem
Life long use Infection, cancers Nephrotoxicity Diabetogenic
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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
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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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Toxicity
Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension
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Calcineurin inhibitors
Cyclosporine Tacrolimus
Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes
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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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Toxicity : Cyclosporine
Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic
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CYP 3A4
Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice Inducers: Rifampicin, Phenytoin
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Tacrolimus
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Toxicity - Tacrolimus
Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections
Drug interaction
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Sirolimus
Inhibits T-cell activation and Proliferation Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression mammalian target of rapamycin (mTOR)
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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
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Everolimus
Shorter half life compared to sirolimus Shorter time taken to reach steady state Similar toxicity, drug interactions
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Azathioprine
6 Thio-IMP
Inhibition of cell proliferation Impairment of lymphocyte function Uses Prevention of organ transplant rejection Rheumatoid arthritis
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Toxicity - Azathioprine
Bone marrow suppressionleukopenia, thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol
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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
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Prophylaxis of transplant rejection Combination: Glucocorticoids Calcineurin Inhibitors Toxicity GI, Hematological
Diarrhea, Leucopenia
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Risk of Infection
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Drug Interaction
Decreased absorption when coadministered with antacids Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion
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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
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Toxicity
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Antibodies
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Antibodies
Anti-CD3 Monoclonal antibody (Muromonab-CD3) Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab) Campath-1H (Alemtuzumab) Infliximab Etanercept Adalimumab Efalizumab
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Anti-TNF Agents
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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
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Muromonab-CD3
Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition
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Uses
Treatment of acute organ transplant rejection Toxicity Cytokine release syndrome High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness Prevention: Steroids
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Daclizumab and Basiliximab Bind to IL-2 receptor on surface of activated T cells Block IL-2 mediated T-cell activation
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Campath-1H (Alemtuzumab)
Targets CD52 expressed on lymphocytes, monocytes, Macrophages Extensive lympholysis Prolonged T & B cell depletion Uses Renal transplantation
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Anti-TNF Agents
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Infliximab
Uses Rheumatoid arthritis Chrons disease fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis Toxicity Infusion reaction fever, urticaria, hypotension, dyspnoea Opportunistic infections TB, RTI, UTI
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Etanercept
Fusion protein Ligand binding portion of Human TNF- receptor fused to Fc portion of human IgG1 Uses Rheumatoid arthritis
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Monoclonal Ab Targeting Lymphocyte Function Associated Antigen Blocks T-cell Adhesion, Activation, Trafficking Uses Organ transplantation Psoriasis
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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)
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Immunostimulants
Interferons Interleukin-2
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Immunization
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Levamisole
Antihelminthic Restores depressed immune function of B, T cells, Monocytes, Macrophages Adjuvant therapy with 5FU in colon cancer
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Toxicity Agranulocytosis
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Thalidomide
Birth defect Contraindicated in women with childbearing potential Enhanced T-cell production of cytokines IL-2, IFN- NK cell-mediated cytotoxicity against tumor cells USE: Multiple myeloma
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Bacillus Calmette-Guerin
Adverse Effects
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Interferons
Antiviral Immunomodulatory activity Bind to cell surface receptors initiate intracellular events
Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis
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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
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Interleukin-2 (aldesleukin)
Proliferation of cellular immunity Lymphocytosis, eosinophilia, release of multiple cytokines TNF, IL-1, IFN-
Uses Metastatic renal cell carcinoma Melanoma Toxicity Cardiovascular: capillary leak syndrome, Hypotension
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Immunization
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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.
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Immune Globulin
Indications Individual is deficient in antibodies immunodeficiency Individual is exposed to an agent, inadequate time for active immunization
Rabies Hepatitis B
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Nonspecific immunoglobulins
Antibody-deficiency disorders
High titers of desired antibody Hepatitis B, Rabies, Tetanus
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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 RBCs Hemolytic disease of newborn
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Immune tolerance
Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness Still experimental
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Summary
Immunosuppresion
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