Immunosuppressive Drugs


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Immunosuppressive Drugs

  1. 1. Immunosuppressive drugs<br />
  2. 2. three-signal model of alloimmune responses<br />Philip F. Halloran:NEngl J Med 2004;351:2715-29<br />
  3. 3. Philip F. Halloran:NEngl J Med 2004;351:2715-29<br />
  4. 4. Classification of Immunosuppressive TherapiesUsed in Organ Transplantation<br />Glucocorticoids<br />Small-molecule drugs<br />Immunophilin-binding drugs<br />Calcineurininhibitors<br />Cyclophilin-binding drugs: cyclosporine,ISA(TX)247<br />FKBP12-binding drugs: tacrolimus,modified release tacrolimus<br />Target-of-rapamycin inhibitors: sirolimus,everolimus<br />Inhibitors of nucleotide synthesis<br />Purine synthesis (IMPDH) inhibitors<br />Mycophenolatemofetil<br />Enteric-coated mycophenolic acid<br />Mizoribine<br />Pyrimidine synthesis (DHODH) inhibitors<br />Leflunomide<br />FK778<br />Antimetabolites: azathioprine<br />Sphingosine-1-phosphate–receptor antagonists:Fingolimod<br />
  5. 5. Protein drugs<br />Depleting antibodies (against T cells, B cells, or both)<br />Polyclonal antibody: horse or rabbit antithymocyte globulin<br />Mouse monoclonal anti-CD3 antibody (muromonab-CD3)<br />Humanized monoclonal anti-CD52 antibody (alemtuzumab)<br />B-cell–depleting monoclonal anti-CD20 antibody (rituximab)<br />Nondepleting antibodies and fusion proteins<br />Humanized or chimeric monoclonal anti-CD25 antibody (daclizumab, basiliximab)<br />Fusion protein with natural binding properties:CTLA-4–Ig Belatacept<br />Intravenous immune globulin<br />
  6. 6. Cyclosporine<br />Neoral : oral formulation of cyclosporine that immediately forms a microemulsion in an aqueous environment<br />Description<br />11-amino-acid cyclic peptide fromTolypocladiuminflatum<br />Mechanism<br />Binds to cyclophilin; complex inhibits calcineurinphosphatase and T-cell activation<br />
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  8. 8. Cyclosporine<br />Prescribed for<br />Kidney, liver, heart organ transplantation used in combination with azathioprine and corticosteroids<br />Rheumatoid Arthritis used in combination with methotrexatein rheumatoid arthritis patients who do not respond adequately to methotrexate alone<br />Psosiasisnonimmunocompromised patients with severe (i.e.,extensiveand/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (eg., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated<br />
  9. 9. Cyclosporine<br />Side effect<br />Nephrotoxicity, hemolytic–uremic syndrome, hypertension, neurotoxicity, gum hyperplasia, skin changes, hirsutism, post-transplantation diabetes mellitus, hyperlipidemia; trough monitoring or checking levels two hours after administration required<br />
  10. 10. ISA 247<br />More potent and less toxic than cyclosporin<br />Clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II)<br />
  11. 11. Tacrolimus (FK506)<br />Prescribed for<br />Liver, kidney<br />Heart transplant (prograft+azathripine+MMF)<br />second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis<br />Sideeffect<br />Effects similar to those of cyclosporine but with a lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia and a higher incidence of post-transplantation diabetes mellitus and neurotoxicity; trough monitoring required<br />Seizures,Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Bullousimpetigo, osteomyelitis, septicemia, Rosacea<br />
  12. 12. Tacrolimus (FK506)<br />Prografcapsule, injection and Protopic ointment<br />Description<br />Macrolide antibiotic from Streptomycestsukubaensis<br />Mechanism<br />Binds to FKBP12; complex inhibits calcineurinphosphatase and T-cell activation<br />reduces T-cell and IL-2 activity<br />
  13. 13. J Am Soc Nephrol 10: 1366–1380, 1999<br />
  14. 14. Tacrolimus (FK506)<br />
  15. 15. N =1645 renal transplant,<br />standard-dose cyclosporine, MMFand corticosteroids<br />Daclizumabinduction,MMF, and corticosteroids, low dose sirolimus<br />Daclizumabinduction,MMF, and corticosteroids, low dose cyclosporin<br />Daclizumabinduction,MMF, and corticosteroids, low dosetacrolimus<br />
  16. 16. Pimecrolimus<br />Elidel – cream 1%<br />Description<br />ascomycinmacrolactamderivative<br />Mechanism<br />Binds to macrophilin-12 and inhibits calcineurin<br />Inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells<br />Prevents the release of inflammatory cytokines and mediators from mast cells<br />Similar mode of action to tacrolimus but is more selective<br />no effect on dendritic (Langerhans) cells<br />lower permeation through the skin than topical steroids or topical tacrolimus<br />
  17. 17. Pimecrolimus<br />Prescribed for<br />second-line therapy for the short- term and non-continuous chronic treatment of mild to moderate atopic dermatitis<br />not indicated for use in children less than 2 years of age <br />Side effect<br />impetigo, skin infection , superinfection (infected atopic dermatitis)<br />Anaphylactic reactions, ocular irritation <br />Lymphomas, basal cell carcinoma, malignant melanoma, squamous cell carcinoma<br />
  18. 18. Sirolimus<br /><ul><li>Rapamycin</li></ul>Description<br />Trienemacrolideantibiotic from Streptomyceshygroscopicusfrom Easter Island (Rapa Nui)<br />Mechanism<br />Binds to FKBP12; complex inhibits target of rapamycin and interleukin- 2–driven T-cell proliferation<br />arresting the cell cycle in the G1 phase<br />
  19. 19.
  20. 20. Sirolimus<br />Prescribed for<br />Renal transplant<br /><ul><li>Sideeffect</li></ul>Hyperlipidemia, increased toxicity of calcineurininhibitors, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, interstitial lung disease; lipid monitoring required; recipients whose risk of rejection is low to moderate can stop cyclosporine treatment two to four months after transplantation<br />
  21. 21. Everolimus<br />Certican : Derivative of Rapamycin<br />Mechanism<br />Works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor<br />lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. <br />This AKT elevation can lead to longer survival in some cell types<br />Prescribed for<br />Heart transplant reduce chronic allograft vasculopathy<br /> Howard J. Eisen: N Engl J Med 2003;349:847-58<br />Advance renal cancer<br />Vascular stent<br />
  22. 22.
  23. 23. Azathioprine<br />Imuran: immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection <br />Description<br />Prodrug that releases 6-mercaptopurine <br />the first immunosuppressive agent to achieve widespread use in organ transplantation<br />Mechanism<br />Purine synthesis inhibitor, inhibiting the proliferation of cells, especially leukocyte<br />Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis; thioguaninederivatives may inhibit purinesynthesis<br />prevents mitosis and proliferation of rapidly dividing cells, such as activated B and T lymphocytes<br />
  24. 24. <ul><li>Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is either inactivated by two enzymes, thiopurine s-methyltransferase (TPMT) and xanthineoxidase (XO), or is further metabolized to thioinosinemonophosphate (TIMP).
  25. 25. Genetic polymorphism involving the inactivating enzyme TPMT
  26. 26. Allopurinol inhibits XO, elevate azathioprine bioavailability by fivefold</li></li></ul><li>Azathioprine<br />Prescribed for<br />FDA :<br />Renal Homotransplantation: Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. <br />Rheumatoid Arthritis: treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms<br />Juvenile Rheumatoid Arthritis<br />Non-FDA : Multiple Sclerosis, Crohn's disease, myasthenia gravis, chronic ulcerative colitis, and autoimmune hepatitis <br />Sideeffect<br />Leukopenia, bone marrow depression, macrocytosis, liver toxicity (uncommon); blood-count monitoring required<br />
  27. 27. Mycophenolatemofetil<br /><ul><li>Cellcept oral and injection
  28. 28. Myfortic : mycophenolate sodium</li></ul>Description<br />Mycophenolicacid from penicillium molds<br />Mechanism<br />Inhibits synthesis of inosinemonophosphatedehydrogenase(IMPDH); blocks purinesynthesis, preventing proliferation of T and B cells<br />
  29. 29.
  30. 30. Mycophenolatemofetil<br />Prescribed for<br /><ul><li>Renal, liver and cardiac transplant
  31. 31. Lupus nephritis</li></ul>Sideeffect<br />GI symptoms (mainly diarrhea), neutropenia, mild anemia; blood-level monitoring not required but may improve efficacy; absorption reduced by cyclosporine<br />lymphomas and other malignancies, particularly of the skin <br />Infection, CMV<br />Progressive Multifocal Leukoencephalopathy (PML) <br />
  32. 32. Mizoribine<br />Bredinin<br />Description<br />isolated from the mould Eupenicilliumbrefeldianum<br />Mechanism<br />Mizoribinemonophosphate (MZP) is the active metabolite<br />Inhibitor of IMP dehydrogenase (IMPDH)<br />
  33. 33. Leflunomide<br />Aravaoral administration as tablets containing 10, 20, or 100 mg<br />Description<br />pyrimidine synthesis inhibitor <br />Mechanism<br />Dihydroorotatedehydrogenase inhibitor<br />antiproliferative activity<br />Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect <br />
  34. 34. Leflunomide<br />
  35. 35. Leflunomide<br />Prescribed for<br />RA: reduction in signs and symptoms, and inhibition of structural damage and improvement in physical function <br /> (loading dose of 100 mg per day for three days only was used followed by 20 mg per day )<br /> Aspirin, NSAIDS and/or low dose corticosteroids may be continued during treatment with ARAVA <br />Psoriatic arthritis, AS<br />Side effect<br />diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash <br />high BP, chest pain and abnormal heartbeats<br />increase the risk to patients of infections<br />
  36. 36. FK778<br />malononitrilamides<br />Description<br />active derivative of leflunomide<br />Mechanism<br />Inhibits pyrimidine synthesis, blocking proliferation of T and B cells<br />Side effect<br />Anemia; other effects not known; in phase 2 trials kidney transplant<br />
  37. 37. Fingolimod<br /><ul><li>FTY720</li></ul>Description<br />Sphingosine-like derivative of myriocin from ascomycete fungus<br />Mechanism<br />Works as an antagonist for sphingosine-1-phosphate receptors on lymphocytes, enhancing homing to lymphoid tissues and preventing egress, causing lymphopenia<br />
  38. 38.
  39. 39.
  40. 40. Fingolimod<br />Prescribed for<br />Renal transplant<br />Multiple sclerosis: reducedthe number of lesions detected on MRI and clinical disease activity<br />(Ludwig KapposN Engl J Med 2006;355:1124-40)<br />Side effect<br />Reversible first-dose bradycardia, potentiated by general anesthetics and beta-blockers; nausea, vomiting, diarrhea, increased liver-enzyme<br />infections, skin cancer and, recently, a case of haemorrhaging focal encephalitis<br />
  41. 41. Muromonab-CD3<br />OrthocloneOKT3<br />Description<br />Murinemonoclonal antibody against CD3 component of T-cell–receptor signal-transduction complex<br />Mechanism<br />monoclonal IgG2a antibody<br />binds to the T cell receptor-CD3-complex (specifically the CD3 epsilon chain) on the surface of circulating T cells, interfering with the receptor-antigen-interaction<br />resulting in a transient activation of T cells, release of cytokines, and blocking of T-cell proliferation and differentiation<br />T-cell function usually returns to normal within approximately 48 hours of discontinuation of therapy<br />
  42. 42.
  43. 43.
  44. 44. Muromonab-CD3<br />Prescribed for<br />Renal, heart and liver transplant<br />Side effect<br />Severe cytokine-release syndrome, pulmonary edema, acute renal failure, gastrointestinal disturbances, changes in central nervous system<br />pyrexia myalgia, nausea and diarrhoea<br />
  45. 45. Alemtuzumab<br />Campath<br />Description<br />Humanized monoclonal antibody against CD52, a 25-to-29-kD membrane protein<br />Mechanism<br />Binds to CD52 on all B and T cells, most monocytes, macrophages, and natural killer cells, causing cell lysisand prolonged depletion<br />
  46. 46. Alemtuzumab<br />Prescribed for<br />CLL, CTCL and T celllymphoma<br />Sideeffect<br />hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash<br />
  47. 47. Rituximab<br />Rituxan, MabThera<br />Description <br />Chimericmonoclonal antibody against membrane-spanning four-domain protein CD20<br />Mechanism<br />Binds to CD20 on B cells and mediates B-cell lysis<br />
  48. 48.
  49. 49. Rituximab<br />Prescribed for<br />Lymphoma, leukemia<br />RA with MTX<br />Renal transplant (especially useful in transplants involving incompatible blood groups)<br />Off label – MS, SLE, autoimmune hemolytic anemia<br />Side effect<br />Infusion reactions, hypersensitivity reactions<br />Infection : HBV, PML<br />Tumor Lysis Syndrome (TLS) in ARF<br />
  50. 50. Daclizumab<br /><ul><li>Zenapax</li></ul>Description<br />Humanized monoclonal antibody against CD25 (interleukin-2– receptor α chain)<br />Mechanism<br />Binds to and blocks the interleukin-2– receptor α chain (CD25 antigen) binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding<br />on activated T cells, depleting them and inhibiting interleukin-2–induced T-cell activation<br />
  51. 51.
  52. 52. Daclizumab<br />Prescribed for<br /><ul><li>Renal, cardiac transplant
  53. 53. MS</li></ul>Sideeffect<br />Hypersensitivity reactions (uncommon)<br />gastrointestinal disorders <br />does not appear to increase the incidence of opportunistic infections or malignancies <br />
  54. 54. Belatacept<br />Description<br />Protein combining B7-binding portion of CTLA-4 with IgGFcregion<br />Mechaniasm<br />Binds to B7 on T cells, preventing CD28 signaling and signal 2<br />Prescribed for<br />Renal transplant<br />
  55. 55.
  56. 56. Abatacept<br />Orencia<br />second-generation belatacept<br />Prescribed for<br />Renal transplant<br />RA, UC, lupus nephritis<br />
  57. 57. CP-690,550<br /><ul><li>JAK3 inhibitor
  58. 58. Phase II treatment RA
  59. 59. Phase II renal transplant</li></li></ul><li>Polyclonalantibody<br />Antithymocyte globulin-equine (Atgam®),Antithymocyte globulin-rabbit (RATG, Thymoglobulin®)<br />Description<br />Polyclonal antibodies are directed against lymphocyte antigens, directed against multiple epitopes<br />
  60. 60. Polyclonalantibody<br />Mechanism<br />agents contain antibodies specific for many common T cell antigens including CD2, CD3, CD4, CD8, CD11a, CD18<br />effectively depletes T-cell concentration in the body through complement-dependent cytolysis and cell mediated opsonization<br />following with T cell clearance from the circulation by the reticuloendothelial system<br />
  61. 61. Polyclonalantibody<br />Sideeffect<br />Leukopenia<br />serum sickness (cross-reactivity with other tissue antigens) <br />adversely affects the ability of the patient to make antibodies against foreign protein <br />thrombocytopenia <br />pruritis<br />fever <br />arthralgias<br />opportunistic infections <br />malignancies <br />
  62. 62.
  63. 63. Immunosuppressive drugs used to treat transplant rejection<br />Calcineurin inhibitors<br />Ciclosporin<br />Tacrolimus<br />mTOR inhibitors<br />Sirolimus<br />Everolimus<br />Anti-proliferatives<br />Azathioprine<br />Mycophenolic acid<br />Corticosteroids<br />Prednisolone<br />Hydrocortisone<br />Antibodies<br />Monoclonal anti-IL-2Rα receptor antibodies <br />Basiliximab<br />Daclizumab<br />Polyclonal anti-T-cell antibodies <br />Anti-thymocyte globulin (ATG) <br />
  64. 64. The IL-2 receptor antagonist daclizumab is approved for use in what condition? <br /> (A) Asthma <br /> (B) Hypereosinophilia<br /> (C) Renal transplant <br /> (D) Non-Hodgkin’s lymphoma <br />
  65. 65. Cyclosporine modulates calcium dependent T cell activation by inhibiting <br /> (A) Cadherin<br /> (B) Calnexin<br /> (C) Calcineurin<br /> (D) Calreticulin<br />