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IMMUNOSUPPRESSION I:

IMMUNOSUPPRESSION I:. Principles and Mechanisms of Current Agents. Stimulus. Activation. Expansion. Rejection. Memory. T Cells Divide Plasma Cells Make Antibody. Effector T Cells Attack the Transplant Humoral Rejection. Immune System Encounters the Transplant Hyperacute

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IMMUNOSUPPRESSION I:

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  1. IMMUNOSUPPRESSION I: Principles and Mechanisms of Current Agents

  2. Stimulus Activation Expansion Rejection Memory T Cells Divide Plasma Cells Make Antibody Effector T Cells Attack the Transplant Humoral Rejection Immune System Encounters the Transplant Hyperacute Rejection T Lymphocytes Are Activated And Make Cytokines Immune System Develops T and B cell memory Events Following T Cell Activation 0 0.5 1 2… 24 hours…. 3-4 days… 7 days...

  3. Pre-Transplant Therapy Antibody Suppression Late Acute Rejection Early Acute Rejection Acute Immune Desensitization Immune Accommodation Induction Therapy Acute Post-Transplant Immunosuppression The Phases of Immunosuppression Chronic Allograft Dysfunction Maintenance Immunosuppression Graft Failure

  4. Signal 2 Costimulation Signal 4 Apoptosis Signal 1 Class II + peptide Signal 3 Cytokine Anti-IL-2Ra OKT3 or Polyclonal Antibodies CD95 TNF-R IL-2 R abg Death Machinery e.g., CD28, CD40L Bax bcl-2 FLIP-L P13-K TCR Complex CD3 +CD4 TAC CsA SIR TOR calcineurin MMF G1 S NFATp IL-2 mRNA IL-2R mRNA Cyclin/CDK AZA STER Calcineurin promoter (IL-2) M G2

  5. Polyclonal Anti-Thymocyte Globulin Campath-1H OKT3 Lymphocyte Depleting Antibody Therapies CD52 CD3

  6. MHC class II TCR Daclizumab (Zenapax®) and Basiliximab (Simulect®) Block the IL-2 Receptor Antigen APC B7 CD4 CD28 IL-2R 1 2 Calcineurin IL-2 IL - 2 gene T Cell

  7. Overview of Maintenance Immunosuppression Costimulatory molecules i.e CD28 and CD40L IL-2 IL-2R b g TCR complex ab TCR, CD3, CD4, etc a CD25 (inducible) Sirolimus:FKBP Kinase activity Apoptosis Cyclosporine:cyclophilin Calmodulin Calcineurin TOR De novo purine synthesis Steroids Phosphatase activity G1 S Tacrolimus:FKBP NFAT AP-1 NF-KB G2 IL-2 gene M Nucleus Azathioprine Mycophenolate Mofetil

  8. Corticosteroids-Molecular Mechanisms IkB binds to NF-kB and prevents it from getting into the nucleus and activating cytokine transcription Steroid CELL NF-kB IkB Steroid receptor AP-1 X IkB promoter IL-2 promoter NUCLEUS

  9. Costimulatory molecules i.e CD28 and CD40L IL-2 IL-2R b g TCR complex ab TCR, CD3, CD4, etc a CD25 (inducible) Kinase activity Apoptosis Cyclosporine:cyclophilin Calmodulin Calcineurin TOR De novo purine synthesis Phosphatase activity G1 S Tacrolimus:FKBP NFAT AP-1 NF-KB G2 IL-2 gene M Nucleus Cyclosporine and Tacrolimus: Calcineurin Inhibitors

  10. Azathioprine and Mycophenolate Mofetil Costimulatory molecules i.e CD28 and CD40L IL-2 IL-2R b g TCR complex ab TCR, CD3, CD4, etc a CD25 (inducible) Kinase activity Apoptosis Calmodulin Calcineurin TOR De novo purine synthesis Phosphatase activity G1 S NFAT AP-1 NF-KB G2 IL-2 gene M Nucleus Azathioprine MycophenolateMofetil

  11. TOR Inhibitors (TORI): Sirolimus/Everolimus Costimulatory molecules i.e CD28 and CD40L IL-2 IL-2R b g TCR complex ab TCR, CD3, CD4, etc a CD25 (inducible) Kinase activity TORI:FKBP Apoptosis Calmodulin Calcineurin TOR De novo purine synthesis Phosphatase activity G1 S NFAT AP-1 NF-KB G2 IL-2 gene M Nucleus

  12. US DeNovo Maintenance Regimensfor Kidney Transplant Recipients UNOS: 11/02

  13. Outcomes of Renal Allografts • Radiation • Prednisone • 6-MP • Cyclosporine Emulsion • Tacrolimus • CY-A • MMF • OKT3 • Dicluzimab • Basiliximab • AZA • Thymoglobulin • Sirolimus • ATGAM ‘60 ‘65 ‘70 ‘75 ‘80 ‘85 ‘90 ‘95 ‘00 Year Adapted from Stewart F, Organ Transplantation, 1999

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