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Immunology and Immunosuppression

Immunology and Immunosuppression. December 8, 2009. Immunology. HLA (Human Leukocyte Antigen) major histocompatibility complex (MHC). Class I molecules (HLA-A, B, C) found on the membrane of all nucleated cells. Class II molecules (HLA-DR, DP, DQ)

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Immunology and Immunosuppression

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  1. Immunology and Immunosuppression December 8, 2009

  2. Immunology • HLA (Human Leukocyte Antigen) • major histocompatibility complex (MHC). • Class I molecules (HLA-A, B, C) • found on the membrane of all nucleated cells. • Class II molecules (HLA-DR, DP, DQ) • expressed by antigen-presenting cells (APCs) • B lymphocytes, monocytes, and dendritic cells • HLA-DR most important

  3. allorecognition • recognition of foreign HLA antigens by the recipient T cells • Indirect/direct pathways • Actives cascade, leading to interleukin-2 (IL-2) gene expression • IL-2 then permits the entire cascade of T-cell activation to proceed

  4. Rejection(4 Types) • Hyperacute • Accelerated Acute • Acute • Chronic

  5. Hyperacute • W/in minutes • Preformed Ab’s • activate the complement cascade • diffuse intravascular coagulation. • ischemic necrosis • Reason for cross-match

  6. Accelerated Acute • First couple of days • Cellular and antibody mediated

  7. Acute • Most common • Days-months • Cell mediated-lymphocytes • symtoms: fever, chills, malaise • Usually w/ abnormal labs • elevated creatinine or elevated transaminases

  8. Chronic Rejection • Months to years • Histology: atrophy, fibrosis and arteriosclerosis • Graft fxn slowly deteroriates

  9. Immunosuppression • Steriods • Calcineurin Inhibitors • Cyclsporine • Tacrolimus (Prograf, FK506) • Non Inhibitors of calcineurin • Sirolimus • Antimetabolites • Inhibit purine synthesis • Azathioprine (Imuran) • Mycophenolate mofetil(Cellcept) • Polyclonal Ab’s • ATGAM • Antithymocyte immunoglobulin • Monoclonal Ab’s • Muromonab-CD3 • IL-2R • Rituximab

  10. Steriods • First line treatment in rejection • Mechanism: inhibit genes for cytokine synthesis • Side: many • Cushingoid facies and habitus • Acne • Mood changes • HTN • Muscle weakness • Glc intolerance • Glaucoma

  11. Calcineurin Inhibitors • Cyclosporine (CSA) • Mechanism: binds cyclophilin • Inhibits cytokine synthesis (IL-2, 3, 4 INF-gamma) • Side: • neuro: HA to seizures • CV: HTN • Lung: interstitial fibrosis • GI • Nephrotoxic • Hyperglycemic, Hyperkalemia • Lots of drug interactions • Tacrolimus • Mechanism: binds FK binding protein • Similar to CSA • Much more potent • Side: • same but more neuro side effects • Lots of drug interactions

  12. Sirolimus • Mechanism: inhibits progression of G1 to S phase in cell cycle • Side: • Neutropenia • Thrombocytopenia • Hyperlipidemia

  13. Azathioprine (Imuran) • Mechanism: inhibts purine synthesis • Active metabolite 6-mercaptopurine • Side: • Leukopenia • Thrombocytopenia • Anemia • Hepatotoxic • GI

  14. Mycophenolate mofetil(Cellcept) • mechanism: Inhibits purine synthesis • Preventing T cell proliferation • More selective than Imuran • side: • Leukopenia • GI disturbances

  15. ATGAM • Equine Polyclonal Ab’s • Mechanism: Ab’s against Ag’s on T cells • Use in Induction • Side: • fever, chills • Leukopenia, thrombocytopenia • Serum sickness

  16. Antithymocyte immunoglobulin(Thymoglobulin) • Rabbit Polyclonal Ab’s • Mechanism: same as ATGAM • Induction • Side: • Leukopenia, thrombocytopenia

  17. Monoclonal Ab’s • Muromonab-CD3 (OKT3) • Binds to CD3: inhibiting T cell receptor complex • Used for severe rejection • Side: fever, chills, HA • Flash pulmonary edema • IL-2R (Basiliximab and Daclizumab) • Anti-CD25 monoclonal Ab’s • induction • Rituximab • Anti-CD20 • Used for posttransplant lymphoproliferative disease

  18. What is a common side effect of tacrolimus? • A: muscle aches • B: hyperkalemia • C: glaucoma • D: anaphylaxis

  19. What is an emergent side effect of OKT3? • A: pulmonary edema • B: arrythmias • C: seizures • D: hyperkalemia

  20. Rituximab is used in what treatment? • A: induction • B: acute rejection • C: posttransplant lymphoproliferative disease • D: chronic rejection

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