Immunopharmacology

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Immunopharmacology

  1. 1. IMMUNOPHARMACOLOGY Ma. Janetth B. Serrano, M.D., DPBA
  2. 2. IMMUNOPHARMACOLOGY <ul><li>2 major components of the immune system: </li></ul><ul><ul><li>INNATE </li></ul></ul><ul><ul><ul><li>Physical – skin, mucus membrane </li></ul></ul></ul><ul><ul><ul><li>Biochemical – complement, lyzosyme </li></ul></ul></ul><ul><ul><ul><li>Cellular – macrophages, neutrophils </li></ul></ul></ul><ul><ul><li>ADAPTIVE </li></ul></ul><ul><ul><ul><li>Antibodies – HUMORAL immunity </li></ul></ul></ul><ul><ul><ul><li>T-lymphocyte – CELL MEDIATED immunity </li></ul></ul></ul>
  3. 3. <ul><li>COMPLEMENTS in Innate Immunity: </li></ul><ul><li>1. C3a, C5a  chemotaxis </li></ul><ul><li>2. C3b  opsonization </li></ul><ul><li>3. C5b, C6, C7, C8, C9  MAC </li></ul>IMMUNOPHARMACOLOGY
  4. 4. IMMUNOPHARMACOLOGY 0psonized bacteria Macrophage APC T lymphocyte IL-2 IL-2 IFN-  Activated Macrophage Activated NK cells Activated Cytotoxic T cell CELL-MEDIATED IMMUNITY B lymphocyte IL-4,IL-5 TH 1 TH 2 Memory B Cells <ul><li>Plasma Cells: </li></ul><ul><li>IgG - IgM </li></ul><ul><li>IgA - IgD </li></ul>HUMORAL IMMUNITY IFN-  TNF-  IFN- 
  5. 5. <ul><li>T-helper cells: </li></ul><ul><li>1. T H 1 subset </li></ul><ul><li>- IFN-  , IL-2, TNF-  </li></ul><ul><li>2. T H 2 subset </li></ul><ul><li>- IL-4, IL-5, IL-6, IL-10 </li></ul>IMMUNOPHARMACOLOGY
  6. 6. <ul><li>ABNORMAL IMMUNE RESPONSES: </li></ul><ul><ul><ul><li>HYPERSENSITIVITY </li></ul></ul></ul><ul><ul><ul><li>AUTOIMMUNITY </li></ul></ul></ul><ul><ul><ul><li>IMMUNODEFICIENCY </li></ul></ul></ul>IMMUNOPHARMACOLOGY
  7. 7. <ul><ul><li>1. Corticosteroids </li></ul></ul><ul><ul><li>2. Cyclosporine </li></ul></ul><ul><ul><li>3. Sirolimus </li></ul></ul><ul><ul><li>4. Tacrolimus </li></ul></ul><ul><ul><li>5. Interferons </li></ul></ul><ul><ul><li>6. TNF-alpha binding drugs </li></ul></ul><ul><ul><li>7. Mycophenolate mofetil </li></ul></ul><ul><ul><li>8. 15-Deoxyspergualin </li></ul></ul><ul><ul><li>9. Thalidomide </li></ul></ul><ul><ul><li>10. Glatiramer </li></ul></ul>Immunosuppressants IMMUNOPHARMACOLOGY
  8. 8. Corticosteroids IMMUNOPHARMACOLOGY
  9. 9. <ul><li>MOA: </li></ul><ul><ul><li>inhibit T-cell proliferation & T-cell dependent immunity </li></ul></ul><ul><ul><li>Inhibit expression of genes encoding cytokines </li></ul></ul><ul><ul><li>Inhibit production of inflammatory mediators </li></ul></ul><ul><li>Affects cell-mediated immunity more than humoral immunity </li></ul>IMMUNOPHARMACOLOGY
  10. 10. <ul><li>Continuous administration: </li></ul><ul><ul><li>↑ fractional catabolic rate of IgG </li></ul></ul><ul><li>Indications: </li></ul><ul><ul><li>Autoimmune disorders </li></ul></ul><ul><ul><ul><li>- autoimmune hemolytic anemia, LE </li></ul></ul></ul><ul><ul><ul><li>- ITP, Inflammatory Bowel Dse,, Hashimoto’s </li></ul></ul></ul><ul><ul><li>Modulate allergic reactions - asthma </li></ul></ul><ul><ul><li>Organ transplantation – rejection crisis </li></ul></ul>IMMUNOPHARMACOLOGY
  11. 11. <ul><li>Immunosuppressive dose: </li></ul><ul><ul><li>10-100 mg/day </li></ul></ul><ul><li>Adverse effects: </li></ul><ul><ul><li>GI bleeding </li></ul></ul><ul><ul><li>adrenal suppression </li></ul></ul><ul><ul><li>fluid retention </li></ul></ul><ul><ul><li>diabetes </li></ul></ul><ul><ul><li>proximal muscle wasting </li></ul></ul><ul><ul><li>superinfections </li></ul></ul>IMMUNOPHARMACOLOGY
  12. 12. Corticosteroids IMMUNOPHARMACOLOGY
  13. 13. Cyclosporin IMMUNOPHARMACOLOGY
  14. 14. <ul><li>Blocks T-cell activation </li></ul><ul><li>binds to cyclophillin  inhibits calcineurin activity  inhibits gene transcription of IL-2, IL-3, IFN  & other factors </li></ul><ul><li>Most commonly used immunosuppresant for renal transplantation </li></ul><ul><li>Indications: </li></ul><ul><ul><li>transplant rejection (kidney, liver, pancreas, cardiac) </li></ul></ul><ul><ul><li>Autoimmune disorders (uveitis, RA, DM type1) </li></ul></ul><ul><li>Toxicities: </li></ul><ul><ul><li>nephrotoxicity, hyperglycemia, hyperlipidemia, osteoporosis, ↑ hair growth, transient liver dysfunction </li></ul></ul>IMMUNOPHARMACOLOGY
  15. 15. Cyclosporin IMMUNOPHARMACOLOGY
  16. 16. Tacrolimus IMMUNOPHARMACOLOGY
  17. 17. <ul><li>Binds to FK-binding protein  inhibits T-cell activation </li></ul><ul><li>10-100 times more potent than cyclosporine </li></ul><ul><li>Liver & kidney transplant </li></ul><ul><li>Oral or IV : t½ = 9-12 hrs </li></ul><ul><li>Toxicity: </li></ul><ul><ul><li>nephrotoxicity, neurotoxicity, hyperglycemia, GI dysfunction </li></ul></ul>IMMUNOPHARMACOLOGY
  18. 18. Tacrolimus IMMUNOPHARMACOLOGY
  19. 19. Sirolimus (rapamycin) IMMUNOPHARMACOLOGY
  20. 20. <ul><li>Binds also to immunophyllin  blocks the response of T-cell to cytokines </li></ul><ul><li>Potent inhibitor of B-cell proliferation & Ig production </li></ul><ul><li>Indications: </li></ul><ul><ul><li>Kidney & heart allografts </li></ul></ul><ul><ul><li>C syclosporin  psoriasis & uveoretinitis </li></ul></ul>IMMUNOPHARMACOLOGY
  21. 21. Sirolimus (rapamycin) IMMUNOPHARMACOLOGY
  22. 22. Interferons IMMUNOPHARMACOLOGY
  23. 23. <ul><li>Type 1: induced by viral inf. </li></ul><ul><ul><li>IFN-alpha  prod. by leukocytes </li></ul></ul><ul><ul><li>IFN-beta  fibroblasts & epithelial cells </li></ul></ul><ul><li>Type 2: IFN-gamma  produced by activated T-lymphocytes </li></ul><ul><li>Indications: cancer </li></ul><ul><li>IFN-   multiple sclerosis </li></ul><ul><li>IFN-   chronic granulomatous disease </li></ul>IMMUNOPHARMACOLOGY
  24. 24. Interferons IMMUNOPHARMACOLOGY
  25. 25. TNF- α binding drugs IMMUNOPHARMACOLOGY
  26. 26. <ul><li>INFLIXIMAB </li></ul><ul><ul><li>Chimeric IgG1 monoclonal antibody with human region & murine regions </li></ul></ul><ul><ul><li>Suppress generation of cytokines </li></ul></ul><ul><ul><li>Crohn’s disease; RA </li></ul></ul><ul><li>ETANERCEPT </li></ul><ul><ul><li>Chimeric protein with human regiom </li></ul></ul><ul><ul><li>Similar MOA with infliximab but shorter half-life </li></ul></ul><ul><ul><li>RA </li></ul></ul>IMMUNOPHARMACOLOGY
  27. 27. TNF- α binding drugs IMMUNOPHARMACOLOGY
  28. 28. Mycophenolate Mofetil IMMUNOPHARMACOLOGY
  29. 29. <ul><li>Inhibits a series of T & B lymphocyte responses </li></ul><ul><li>Inhibit de novo pathway of purine synthesis </li></ul><ul><li>Renal & heart transplantation </li></ul><ul><li>Mizoribine – inh. nucleotide synthesis PW; kidney transplants </li></ul><ul><li>Brequinar Sodium – inh. de novo pathway of pyrimidine synthesi; cancer & organ transplantation </li></ul>IMMUNOPHARMACOLOGY
  30. 30. Mycophenolate Mofetil IMMUNOPHARMACOLOGY
  31. 31. 15-Deoxyspergualin IMMUNOPHARMACOLOGY
  32. 32. <ul><li>Potent antimonocytic & antilymphocytic effect </li></ul><ul><li>Inhibits T & B lymphocyte response </li></ul><ul><li>Renal transplants; pancreas & heart transplants </li></ul>IMMUNOPHARMACOLOGY
  33. 33. 15-Deoxyspergualin IMMUNOPHARMACOLOGY
  34. 34. Thalidomide IMMUNOPHARMACOLOGY
  35. 35. <ul><li>Sedative drug </li></ul><ul><li>Favors TH2 over TH1 </li></ul><ul><li>Suppress TNF- α production </li></ul><ul><li>Antiangiogenesis action: teratogenicity & anticancer </li></ul><ul><li>Indications </li></ul><ul><ul><li>Erythema nodosum leprosum (skin manifestations of SLE) </li></ul></ul><ul><ul><li>Lung transplantation </li></ul></ul>IMMUNOPHARMACOLOGY
  36. 36. Thalidomide IMMUNOPHARMACOLOGY
  37. 37. Glatiramer IMMUNOPHARMACOLOGY
  38. 38. <ul><li>Relapsing-remitting form of multiple sclerosis </li></ul><ul><li>Subcutaneous injection </li></ul><ul><li>Toxicities: </li></ul><ul><ul><li>Transient post-injection reaction </li></ul></ul>IMMUNOPHARMACOLOGY
  39. 39. Glatiramer IMMUNOPHARMACOLOGY
  40. 40. <ul><li>1. Azathioprine </li></ul><ul><li>2. Leflunomide </li></ul><ul><li>3. Cyclophosphamide </li></ul>IMMUNOPHARMACOLOGY CYTOTOXIC Agents:
  41. 41. Azathioprine IMMUNOPHARMACOLOGY
  42. 42. <ul><li>Metabolized to 6-mercaptopurines </li></ul><ul><li>Inhibit purine synthesis  interferes with nucleic acid metabolism  inhibits cellular & humoral responses </li></ul><ul><li>Highly teratogenic </li></ul><ul><li>Well absorbed from GI tract </li></ul>IMMUNOPHARMACOLOGY
  43. 43. <ul><li>Renal allograft, AGN, SLE(renal), RA, Crohn’s disease </li></ul><ul><li>Prednisone-resistant antibody-mediated ITP </li></ul><ul><li>Autoimmune hemolytic anemia </li></ul><ul><li>Toxicities: </li></ul><ul><ul><li>Bone marrow suppression </li></ul></ul><ul><ul><li>GI disturbances: N&V, diarrhea </li></ul></ul><ul><ul><li>Skin rashes, drug fever, hepatic dysfunction </li></ul></ul>IMMUNOPHARMACOLOGY
  44. 44. Azathioprine IMMUNOPHARMACOLOGY
  45. 45. Leflunomide IMMUNOPHARMACOLOGY
  46. 46. <ul><li>Prodrug of an inhibitor of pyrimidine synthesis </li></ul><ul><li>Inhibits lymphoid cells </li></ul><ul><li>Orally active </li></ul><ul><li>RA </li></ul><ul><li>Toxicities: </li></ul><ul><ul><li>Headache, nausea & diarrhea </li></ul></ul><ul><ul><li>Hepatic dysfunction, renal impairment </li></ul></ul><ul><li>Teratogenic </li></ul>IMMUNOPHARMACOLOGY
  47. 47. Leflunomide IMMUNOPHARMACOLOGY
  48. 48. Cyclophosphamide IMMUNOPHARMACOLOGY
  49. 49. <ul><li>Most potent immunosuppressive drug </li></ul><ul><li>Destroys proliferating lymphoid cells </li></ul><ul><li>Autoimmune disorders: SLE </li></ul><ul><li>Acquired factor XIII antibodies </li></ul><ul><li>Bleeding syndromes </li></ul><ul><li>Toxicities: </li></ul><ul><ul><li>Pancytopenia, hemorrhagic cystitis </li></ul></ul>IMMUNOPHARMACOLOGY
  50. 50. Cyclophosphamide IMMUNOPHARMACOLOGY
  51. 51. Antibodies as Immunosuppressive Agents <ul><li>Antilymphocytic antibody </li></ul><ul><li>Immune Globulin IV </li></ul><ul><li>Hyperimmune Immunoglobulins </li></ul><ul><li>Monoclonal Antibodies </li></ul><ul><li>Rh o (D) Immune Globulin Micro-Dose </li></ul><ul><ul><li>Prevention of hemolytic disease of the newborn </li></ul></ul><ul><ul><li>Given to mother within 72 hrs after delivery of an Rh-negative baby </li></ul></ul>IMMUNOPHARMACOLOGY
  52. 52. <ul><li>1.Muromonab- CD3 </li></ul><ul><li>2. Palivizumab </li></ul><ul><li>3. Rituxumab </li></ul><ul><li>4.Trastuzumab </li></ul>IMMUNOPHARMACOLOGY MONOCLONAL ANTIBODIES :
  53. 53. Muromonab-CD3 IMMUNOPHARMACOLOGY
  54. 54. <ul><li>A T-cell specific antibody </li></ul><ul><li>Renal transplantation, heart / renal </li></ul>IMMUNOPHARMACOLOGY Muromonab-CD3
  55. 55. Muromonab-CD3 IMMUNOPHARMACOLOGY
  56. 56. <ul><li>2. Palivizumab </li></ul><ul><li>3. Rituxumab </li></ul><ul><li>4.Trastuzumab </li></ul>IMMUNOPHARMACOLOGY MONOCLONAL ANTIBODIES :
  57. 57. <ul><li>P – RSV </li></ul><ul><li>R – follicular B-cell non-hodgekins lymphma </li></ul><ul><li>T – metastatic breast CA </li></ul>IMMUNOPHARMACOLOGY
  58. 58. Interferon-alpha
  59. 59. IMMUNOMODULATORS <ul><li>CYTOKINES </li></ul>- hairy cell leukemia - chronic myelogenous leukemia - malignant melanoma - Kaposi’s sarcoma - anticancer  renal cell CA, carcinoid syndrome, T cell leukemia
  60. 60. Interferon-alpha
  61. 61. IMMUNOMODULATORS <ul><li>CYTOKINES </li></ul>GM-CSF Interferons & IL-2 TNF-alpha Interleukin-2 Interferon-gamma Interferon-beta
  62. 62. IMMUNOMODULATORS <ul><li>CYTOKINES </li></ul>Melanoma and Prostate cancer (+) effects in response to Hep B vaccine Malignant melanoma Soft tissue sarcoma of extremities Metastatic renal cell CA Malignant melanoma Chronic granulomatous disease Relapsing type multiple sclerosis
  63. 63. IMMUNOMODULATORS <ul><li>CYTOKINES </li></ul>GM-CSF Interferons & IL-2 TNF-alpha Interleukin-2 Interferon-gamma Interferon-beta
  64. 64. LEVAMISOLE IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  65. 65. IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY - antiparasitic agent - potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA - other uses: > hodgkin’s lymphoma > RA
  66. 66. LEVAMISOLE IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  67. 67. BCG (Bacille-Camille-Guarin) IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  68. 68. IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY - immunization against tuberculosis - Adjuvant in intravesical therapy for SF bladder CA
  69. 69. BCG (Bacille-Camille-Guarin) IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY
  70. 70. IMMUNOPHARMACOLOGY IMMUNOMODULATORS IMMUNOPHARMACOLOGY <ul><li>HIV: </li></ul><ul><li>- Inosiplex </li></ul><ul><li>- Diethylcarbamate (DTC) </li></ul><ul><li>DiGeorge Syndrome of T cell deficiency </li></ul><ul><li>- give THYMOSIN </li></ul>

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