1. Immunology and Immunosuppression December 8, 2009

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

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

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

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

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

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

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

9. Immunosuppression Steriods Steriods Calcineurin Inhibitors Calcineurin Inhibitors CyclsporineCyclsporine Tacrolimus (Prograf, FK506)Tacrolimus (Prograf, FK506) Non Inhibitors of calcineurin Non Inhibitors of calcineurin SirolimusSirolimus Antimetabolites Antimetabolites Inhibit purine synthesisInhibit purine synthesis Azathioprine (Imuran)Azathioprine (Imuran) Mycophenolate mofetil(Cellcept)Mycophenolate mofetil(Cellcept) Polyclonal Ab’s Polyclonal Ab’s ATGAMATGAM Antithymocyte immunoglobulinAntithymocyte immunoglobulin Monoclonal Ab’s Monoclonal Ab’s Muromonab-CD3Muromonab-CD3 IL-2RIL-2R RituximabRituximab

10. Steriods First line treatment in rejection First line treatment in rejection Mechanism: inhibit genes for cytokine synthesis Mechanism: inhibit genes for cytokine synthesis Side: many Side: many Cushingoid facies and habitusCushingoid facies and habitus AcneAcne Mood changesMood changes HTNHTN Muscle weaknessMuscle weakness Glc intoleranceGlc intolerance GlaucomaGlaucoma

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

12. Sirolimus Mechanism: inhibits progression of G1 to S phase in cell cycle Mechanism: inhibits progression of G1 to S phase in cell cycle Side: Side: NeutropeniaNeutropenia ThrombocytopeniaThrombocytopenia HyperlipidemiaHyperlipidemia

13. Azathioprine (Imuran) Mechanism: inhibts purine synthesis Mechanism: inhibts purine synthesis Active metabolite 6-mercaptopurine Active metabolite 6-mercaptopurine Side: Side: LeukopeniaLeukopenia ThrombocytopeniaThrombocytopenia AnemiaAnemia HepatotoxicHepatotoxic GIGI

14. Mycophenolate mofetil(Cellcept) mechanism: Inhibits purine synthesis mechanism: Inhibits purine synthesis Preventing T cell proliferationPreventing T cell proliferation More selective than ImuranMore selective than Imuran side: side: LeukopeniaLeukopenia GI disturbancesGI disturbances

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

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

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

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

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

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