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Immunosuppression (IS) 1954 – 2005

Immunosuppression (IS) 1954 – 2005. Malononitrilamides (FK778). Everolimus (RAD). Sirolimus (SRL). Mycophenolate mofetil (MMF). Leflunomide. Tacrolimus (Tac). FTY720. Cyclosporine A (CsA). Azathioprine (Aza). Steroids. OKT 3. CTLA4Ig. Campath1H. monoclonal antibodies.

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Immunosuppression (IS) 1954 – 2005

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  1. Immunosuppression (IS) 1954 – 2005 Malononitrilamides (FK778) Everolimus (RAD) Sirolimus (SRL) Mycophenolate mofetil (MMF) Leflunomide Tacrolimus (Tac) FTY720 Cyclosporine A (CsA) Azathioprine (Aza) Steroids OKT 3 CTLA4Ig Campath1H monoclonal antibodies polyclonal antibodies TBI - radiation 1950 1960 1970 1980 1990 2000 2010

  2. Targets of different IS drugs Co-stimulatorySignal AntigenicSignal APC IL-2 receptor TCR DaclizumabBasiliximab m-TOR (SRL/ EVL) Ca2+ T-cell De novopurine synthesis CNIs IL-2 AZA P ActivatedCalcineurin MMF S G1 NFAT CellCycle Steroid NFAT M G2 + IL-2 gene promotor

  3. MMF - Mechanism of action • MMF selectively and reversibly inhibits IMPDH (B- and T-lymphocytes); it’s not incorporated into DNA • AZA blocks proliferation of all rapidly dividing cells in a non-selective way and is incorporated into DNA (mutagenic), explaining the adverse effects and limiting the doses needed for accurate immunosuppression

  4. MMF - Mechanism of action Inhibition of de novo purine synthesis dGTP DNA De novo pathway RNA dGDP IMPDH GTP GMP IMP PRPP Glycoprotein synthesis HGPRTase MPA MMF Salvage pathway Guanine

  5. MMF - Mechanism of action Dependence on de novo synthesis Dependence on major salvage pathway Erythroid precursors intestinal epithelial cells Promonocytes Lymphocytes Neurons

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