1. Immunosuppressive drugs

2. three-signal model of alloimmune responses Philip F. Halloran:NEngl J Med 2004;351:2715-29

3. Philip F. Halloran:NEngl J Med 2004;351:2715-29

4. Classification of Immunosuppressive TherapiesUsed in Organ Transplantation Glucocorticoids Small-molecule drugs Immunophilin-binding drugs Calcineurininhibitors Cyclophilin-binding drugs: cyclosporine,ISA(TX)247 FKBP12-binding drugs: tacrolimus,modified release tacrolimus Target-of-rapamycin inhibitors: sirolimus,everolimus Inhibitors of nucleotide synthesis Purine synthesis (IMPDH) inhibitors Mycophenolatemofetil Enteric-coated mycophenolic acid Mizoribine Pyrimidine synthesis (DHODH) inhibitors Leflunomide FK778 Antimetabolites: azathioprine Sphingosine-1-phosphate–receptor antagonists:Fingolimod

5. Protein drugs Depleting antibodies (against T cells, B cells, or both) Polyclonal antibody: horse or rabbit antithymocyte globulin Mouse monoclonal anti-CD3 antibody (muromonab-CD3) Humanized monoclonal anti-CD52 antibody (alemtuzumab) B-cell–depleting monoclonal anti-CD20 antibody (rituximab) Nondepleting antibodies and fusion proteins Humanized or chimeric monoclonal anti-CD25 antibody (daclizumab, basiliximab) Fusion protein with natural binding properties:CTLA-4–Ig Belatacept Intravenous immune globulin

6. Cyclosporine Neoral : oral formulation of cyclosporine that immediately forms a microemulsion in an aqueous environment Description 11-amino-acid cyclic peptide fromTolypocladiuminflatum Mechanism Binds to cyclophilin; complex inhibits calcineurinphosphatase and T-cell activation

8. Cyclosporine Prescribed for Kidney, liver, heart organ transplantation used in combination with azathioprine and corticosteroids Rheumatoid Arthritis used in combination with methotrexatein rheumatoid arthritis patients who do not respond adequately to methotrexate alone 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

9. Cyclosporine Side effect 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

10. ISA 247 More potent and less toxic than cyclosporin Clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II)

11. Tacrolimus (FK506) Prescribed for Liver, kidney Heart transplant (prograft+azathripine+MMF) second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis Sideeffect 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 Seizures,Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Bullousimpetigo, osteomyelitis, septicemia, Rosacea

12. Tacrolimus (FK506) Prografcapsule, injection and Protopic ointment Description Macrolide antibiotic from Streptomycestsukubaensis Mechanism Binds to FKBP12; complex inhibits calcineurinphosphatase and T-cell activation reduces T-cell and IL-2 activity

13. J Am Soc Nephrol 10: 1366–1380, 1999

14. Tacrolimus (FK506)

15. N =1645 renal transplant, standard-dose cyclosporine, MMFand corticosteroids Daclizumabinduction,MMF, and corticosteroids, low dose sirolimus Daclizumabinduction,MMF, and corticosteroids, low dose cyclosporin Daclizumabinduction,MMF, and corticosteroids, low dosetacrolimus

16. Pimecrolimus Elidel – cream 1% Description ascomycinmacrolactamderivative Mechanism Binds to macrophilin-12 and inhibits calcineurin Inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells Prevents the release of inflammatory cytokines and mediators from mast cells Similar mode of action to tacrolimus but is more selective no effect on dendritic (Langerhans) cells lower permeation through the skin than topical steroids or topical tacrolimus

17. Pimecrolimus Prescribed for second-line therapy for the short- term and non-continuous chronic treatment of mild to moderate atopic dermatitis not indicated for use in children less than 2 years of age Side effect impetigo, skin infection , superinfection (infected atopic dermatitis) Anaphylactic reactions, ocular irritation Lymphomas, basal cell carcinoma, malignant melanoma, squamous cell carcinoma

21. Everolimus Certican : Derivative of Rapamycin Mechanism Works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor 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. This AKT elevation can lead to longer survival in some cell types Prescribed for Heart transplant reduce chronic allograft vasculopathy Howard J. Eisen: N Engl J Med 2003;349:847-58 Advance renal cancer Vascular stent

23. Azathioprine Imuran: immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection Description Prodrug that releases 6-mercaptopurine the first immunosuppressive agent to achieve widespread use in organ transplantation Mechanism Purine synthesis inhibitor, inhibiting the proliferation of cells, especially leukocyte Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis; thioguaninederivatives may inhibit purinesynthesis prevents mitosis and proliferation of rapidly dividing cells, such as activated B and T lymphocytes

25. Genetic polymorphism involving the inactivating enzyme TPMT

28. Myfortic : mycophenolate sodiumDescription Mycophenolicacid from penicillium molds Mechanism Inhibits synthesis of inosinemonophosphatedehydrogenase(IMPDH); blocks purinesynthesis, preventing proliferation of T and B cells

31. Lupus nephritisSideeffect GI symptoms (mainly diarrhea), neutropenia, mild anemia; blood-level monitoring not required but may improve efficacy; absorption reduced by cyclosporine lymphomas and other malignancies, particularly of the skin Infection, CMV Progressive Multifocal Leukoencephalopathy (PML)

32. Mizoribine Bredinin Description isolated from the mould Eupenicilliumbrefeldianum Mechanism Mizoribinemonophosphate (MZP) is the active metabolite Inhibitor of IMP dehydrogenase (IMPDH)

33. Leflunomide Aravaoral administration as tablets containing 10, 20, or 100 mg Description pyrimidine synthesis inhibitor Mechanism Dihydroorotatedehydrogenase inhibitor antiproliferative activity Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect

34. Leflunomide

35. Leflunomide Prescribed for RA: reduction in signs and symptoms, and inhibition of structural damage and improvement in physical function (loading dose of 100 mg per day for three days only was used followed by 20 mg per day ) Aspirin, NSAIDS and/or low dose corticosteroids may be continued during treatment with ARAVA Psoriatic arthritis, AS Side effect diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash high BP, chest pain and abnormal heartbeats increase the risk to patients of infections

36. FK778 malononitrilamides Description active derivative of leflunomide Mechanism Inhibits pyrimidine synthesis, blocking proliferation of T and B cells Side effect Anemia; other effects not known; in phase 2 trials kidney transplant

40. Fingolimod Prescribed for Renal transplant Multiple sclerosis: reducedthe number of lesions detected on MRI and clinical disease activity (Ludwig KapposN Engl J Med 2006;355:1124-40) Side effect Reversible first-dose bradycardia, potentiated by general anesthetics and beta-blockers; nausea, vomiting, diarrhea, increased liver-enzyme infections, skin cancer and, recently, a case of haemorrhaging focal encephalitis

41. Muromonab-CD3 OrthocloneOKT3 Description Murinemonoclonal antibody against CD3 component of T-cell–receptor signal-transduction complex Mechanism monoclonal IgG2a antibody 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 resulting in a transient activation of T cells, release of cytokines, and blocking of T-cell proliferation and differentiation T-cell function usually returns to normal within approximately 48 hours of discontinuation of therapy

44. Muromonab-CD3 Prescribed for Renal, heart and liver transplant Side effect Severe cytokine-release syndrome, pulmonary edema, acute renal failure, gastrointestinal disturbances, changes in central nervous system pyrexia myalgia, nausea and diarrhoea

45. Alemtuzumab Campath Description Humanized monoclonal antibody against CD52, a 25-to-29-kD membrane protein Mechanism Binds to CD52 on all B and T cells, most monocytes, macrophages, and natural killer cells, causing cell lysisand prolonged depletion

46. Alemtuzumab Prescribed for CLL, CTCL and T celllymphoma Sideeffect hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash

47. Rituximab Rituxan, MabThera Description Chimericmonoclonal antibody against membrane-spanning four-domain protein CD20 Mechanism Binds to CD20 on B cells and mediates B-cell lysis

49. Rituximab Prescribed for Lymphoma, leukemia RA with MTX Renal transplant (especially useful in transplants involving incompatible blood groups) Off label – MS, SLE, autoimmune hemolytic anemia Side effect Infusion reactions, hypersensitivity reactions Infection : HBV, PML Tumor Lysis Syndrome (TLS) in ARF

53. MSSideeffect Hypersensitivity reactions (uncommon) gastrointestinal disorders does not appear to increase the incidence of opportunistic infections or malignancies

54. Belatacept Description Protein combining B7-binding portion of CTLA-4 with IgGFcregion Mechaniasm Binds to B7 on T cells, preventing CD28 signaling and signal 2 Prescribed for Renal transplant

56. Abatacept Orencia second-generation belatacept Prescribed for Renal transplant RA, UC, lupus nephritis

58. Phase II treatment RA

60. Polyclonalantibody Mechanism agents contain antibodies specific for many common T cell antigens including CD2, CD3, CD4, CD8, CD11a, CD18 effectively depletes T-cell concentration in the body through complement-dependent cytolysis and cell mediated opsonization following with T cell clearance from the circulation by the reticuloendothelial system

61. Polyclonalantibody Sideeffect Leukopenia serum sickness (cross-reactivity with other tissue antigens) adversely affects the ability of the patient to make antibodies against foreign protein thrombocytopenia pruritis fever arthralgias opportunistic infections malignancies

63. Immunosuppressive drugs used to treat transplant rejection Calcineurin inhibitors Ciclosporin Tacrolimus mTOR inhibitors Sirolimus Everolimus Anti-proliferatives Azathioprine Mycophenolic acid Corticosteroids Prednisolone Hydrocortisone Antibodies Monoclonal anti-IL-2Rα receptor antibodies Basiliximab Daclizumab Polyclonal anti-T-cell antibodies Anti-thymocyte globulin (ATG)

64. The IL-2 receptor antagonist daclizumab is approved for use in what condition? (A) Asthma (B) Hypereosinophilia (C) Renal transplant (D) Non-Hodgkin’s lymphoma

65. Cyclosporine modulates calcium dependent T cell activation by inhibiting (A) Cadherin (B) Calnexin (C) Calcineurin (D) Calreticulin