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IMMUNOPHARMACOLOGY

IMMUNOPHARMACOLOGY. Ma. Janetth B. Serrano, M.D., DPBA. IMMUNOPHARMACOLOGY. 2 major components of the immune system: INNATE Physical – skin, mucus membrane Biochemical – complement, lyzosyme Cellular – macrophages, neutrophils ADAPTIVE Antibodies – HUMORAL immunity

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IMMUNOPHARMACOLOGY

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  1. IMMUNOPHARMACOLOGY Ma. Janetth B. Serrano, M.D., DPBA

  2. IMMUNOPHARMACOLOGY • 2 major components of the immune system: • INNATE • Physical – skin, mucus membrane • Biochemical – complement, lyzosyme • Cellular – macrophages, neutrophils • ADAPTIVE • Antibodies – HUMORAL immunity • T-lymphocyte – CELL MEDIATED immunity

  3. IMMUNOPHARMACOLOGY COMPLEMENTS in Innate Immunity: 1. C3a, C5a  chemotaxis 2. C3b  opsonization 3. C5b, C6, C7, C8, C9  MAC

  4. IMMUNOPHARMACOLOGY 0psonized bacteria Macrophage APC B lymphocyte T lymphocyte IL-4,IL-5 IL-2 IL-2 TH1 TH2 IFN- TNF- IFN- IFN- • Plasma Cells: • IgG - IgM • IgA - IgD Activated Macrophage Activated Cytotoxic T cell Activated NK cells Memory B Cells CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY

  5. IMMUNOPHARMACOLOGY T-helper cells: 1. TH1 subset - IFN- , IL-2, TNF- 2. TH2 subset - IL-4, IL-5, IL-6, IL-10

  6. IMMUNOPHARMACOLOGY ABNORMAL IMMUNE RESPONSES: • HYPERSENSITIVITY • AUTOIMMUNITY • IMMUNODEFICIENCY

  7. Immunosuppressants IMMUNOPHARMACOLOGY 1. Corticosteroids 2. Cyclosporine 3. Sirolimus 4. Tacrolimus 5. Interferons 6. TNF-alpha binding drugs 7. Mycophenolate mofetil 8. 15-Deoxyspergualin 9. Thalidomide 10. Glatiramer

  8. Corticosteroids IMMUNOPHARMACOLOGY • MOA: • inhibit T-cell proliferation & T-cell dependent immunity • Inhibit expression of genes encoding cytokines • Inhibit production of inflammatory mediators • Affects cell-mediated immunity more than humoral immunity

  9. IMMUNOPHARMACOLOGY Corticosteroids • Continuous administration: • ↑ fractional catabolic rate of IgG • Indications: • Autoimmune disorders - autoimmune hemolytic anemia, LE - ITP, Inflammatory Bowel Dse,, Hashimoto’s • Modulate allergic reactions - asthma • Organ transplantation – rejection crisis

  10. IMMUNOPHARMACOLOGY Corticosteroids • Immunosuppressive dose: • 10-100 mg/day • Adverse effects: • GI bleeding • adrenal suppression • fluid retention • diabetes • proximal muscle wasting • superinfections

  11. IMMUNOPHARMACOLOGY Cyclosporin • Blocks T-cell activation • binds to cyclophillin  inhibits calcineurinactivity  inhibits gene transcription of IL-2, IL-3, IFN & other factors • Most commonly used immunosuppresant for renal transplantation • Indications: • transplant rejection (kidney, liver, pancreas, cardiac) • Autoimmune disorders (uveitis, RA, DM type1) • Toxicities: • nephrotoxicity, hyperglycemia, hyperlipidemia, osteoporosis, ↑ hair growth, transient liver dysfunction

  12. Tacrolimus IMMUNOPHARMACOLOGY • Binds to FK-binding protein  inhibits T-cell activation • 10-100 times more potent than cyclosporine • Liver & kidney transplant • Oral or IV : t½ = 9-12 hrs • Toxicity: • nephrotoxicity, neurotoxicity, hyperglycemia, GI dysfunction

  13. IMMUNOPHARMACOLOGY Sirolimus (rapamycin) • Binds also to immunophyllin  blocks the response of T-cell to cytokines • Potent inhibitor of B-cell proliferation & Ig production • Indications: • Kidney & heart allografts • C syclosporin  psoriasis & uveoretinitis

  14. IMMUNOPHARMACOLOGY Interferons • Type 1: induced by viral inf. • IFN-alpha  prod. by leukocytes • IFN-beta  fibroblasts & epithelial cells • Type 2: IFN-gamma  produced by activated T-lymphocytes • Indications: cancer • IFN-  multiple sclerosis • IFN- chronic granulomatous disease

  15. IMMUNOPHARMACOLOGY TNF-α binding drugs • INFLIXIMAB • Chimeric IgG1 monoclonal antibody with human region & murine regions • Suppress generation of cytokines • Crohn’s disease; RA • ETANERCEPT • Chimeric protein with human regiom • Similar MOA with infliximab but shorter half-life • RA

  16. IMMUNOPHARMACOLOGY Mycophenolate Mofetil • Inhibits a series of T & B lymphocyte responses • Inhibit de novo pathway of purine synthesis • Renal & heart transplantation • Mizoribine – inh. nucleotide synthesis PW; kidney transplants • Brequinar Sodium – inh. de novo pathway of pyrimidine synthesi; cancer & organ transplantation

  17. IMMUNOPHARMACOLOGY 15-Deoxyspergualin • Potent antimonocytic & antilymphocytic effect • Inhibits T & B lymphocyte response • Renal transplants; pancreas & heart transplants

  18. IMMUNOPHARMACOLOGY Thalidomide • Sedative drug • Favors TH2 over TH1 • Suppress TNF-α production • Antiangiogenesis action: teratogenicity & anticancer • Indications • Erythema nodosum leprosum (skin manifestations of SLE) • Lung transplantation

  19. IMMUNOPHARMACOLOGY Glatiramer • Relapsing-remitting form of multiple sclerosis • Subcutaneous injection • Toxicities: • Transient post-injection reaction

  20. IMMUNOPHARMACOLOGY CYTOTOXIC Agents: 1. Azathioprine 2. Leflunomide 3. Cyclophosphamide

  21. IMMUNOPHARMACOLOGY Azathioprine • Metabolized to 6-mercaptopurines • Inhibit purine synthesis interferes with nucleic acid metabolism  inhibits cellular & humoral responses • Highly teratogenic • Well absorbed from GI tract

  22. IMMUNOPHARMACOLOGY Azathioprine • Renal allograft, AGN, SLE(renal), RA, Crohn’s disease • Prednisone-resistant antibody-mediated ITP • Autoimmune hemolytic anemia • Toxicities: • Bone marrow suppression • GI disturbances: N&V, diarrhea • Skin rashes, drug fever, hepatic dysfunction

  23. IMMUNOPHARMACOLOGY Leflunomide • Prodrug of an inhibitor of pyrimidine synthesis • Inhibits lymphoid cells • Orally active • RA • Toxicities: • Headache, nausea & diarrhea • Hepatic dysfunction, renal impairment • Teratogenic

  24. IMMUNOPHARMACOLOGY Cyclophosphamide • Most potent immunosuppressive drug • Destroys proliferating lymphoid cells • Autoimmune disorders: SLE • Acquired factor XIII antibodies • Bleeding syndromes • Toxicities: • Pancytopenia, hemorrhagic cystitis

  25. Antibodies as Immunosuppressive Agents IMMUNOPHARMACOLOGY • Antilymphocytic antibody • Immune Globulin IV • Hyperimmune Immunoglobulins • Monoclonal Antibodies • Rho(D) Immune Globulin Micro-Dose • Prevention of hemolytic disease of the newborn • Given to mother within 72 hrs after delivery of an Rh-negative baby

  26. IMMUNOPHARMACOLOGY MONOCLONALANTIBODIES: 1.Muromonab- CD3 2. Palivizumab 3. Rituxumab 4.Trastuzumab

  27. IMMUNOPHARMACOLOGY Muromonab-CD3 • A T-cell specific antibody • Renal transplantation, heart / renal

  28. IMMUNOPHARMACOLOGY • Palivizumab – RSV • Rituximab – follicular B-cell non-hodgekins lymphma • Trastuzumab – metastatic breast CA

  29. IMMUNOMODULATORS • CYTOKINES • Interferon-alpha: - hairy cell leukemia - chronic myelogenous leukemia - malignant melanoma - Kaposi’s sarcoma - anticancer  renal cell CA, carcinoid syndrome, T cell leukemia

  30. IMMUNOMODULATORS • CYTOKINES

  31. IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY IMMUNOMODULATORS • LEVAMISOLE: - antiparasitic agent - potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA - other uses: > hodgkin’s lymphoma > RA

  32. IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY IMMUNOMODULATORS • BCG (Bacille-Camille-Guarin): - immunization against tuberculosis - Adjuvant in intravesical therapy for SF bladder CA

  33. IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY IMMUNOMODULATORS • HIV: - Inosiplex - Diethylcarbamate (DTC) • DiGeorge Syndrome of T cell deficiency - give THYMOSIN

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