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History of immunosuppressants

History of immunosuppressants. Dr. 1 st successful kidney transplant. Dec 23, 1954 Peter Bent Brigham Hospital, Boston MA Dr. Joseph Murray 23 yr old identical twin brothers No immunosuppression used d. 1962 due to disease recurrence (glomerulonephritis). N Engl J Med 2004;351:2761-6.

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History of immunosuppressants

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  1. History of immunosuppressants Dr.

  2. 1st successful kidney transplant • Dec 23, 1954 • Peter Bent Brigham Hospital, Boston MA • Dr. Joseph Murray • 23 yr old identical twin brothers • No immunosuppression used • d. 1962 due to disease recurrence (glomerulonephritis) N Engl J Med 2004;351:2761-6

  3. History of immunosuppression intransplantation

  4. Goals of immunosuppression (IMS) • To prevent allograft rejection • To prolong allograft functional life • To optimise allograft function • Prolong patient survival • Improve patient quality of life • To minimize toxicity of IMS agents • immunodeficiency complications • non-immune toxicities

  5. Transplantation and the immunesystem • Recognition of allograft as non-self • Donor and recipient antigen presenting cells (APC’s = dendritic cells, macrophages) • Present donor antigen to host T-lymphocyte Key event:= T-lymphocyte activation

  6. Immunosuppression:3 ways to achieve • Depletion of lymphocytes • Polyclonal antibodies (horse, rabbit anti-thymocyte globulin) • Mouse monoclonal anti-CD3 antibody (OKT3) • Humanized monoclonal anti-CD52 (alemtuzumab) • B-lymphocyte monoclonal anti-CD20 (rituximab) • Diversion of lymphocyte traffic • Blocking of lymphocyte response NEJM 2004;351:2715-29.

  7. Immune system:3 signal model of T-cell activation

  8. Signal 1: Antigen-specific signal • Donor antigen is presented on APC (antigen presenting cell) • T-cell recognized antigen as “non-self” • Complex formed between MHC-Antigen-Tcell receptor (TCR) • Immune signal is transduced through CD3 complex N Engl J Med 2004;351:2715-29.

  9. Signal 2: Non-antigen-specificco-stimulatory signal • Binding of co-receptors between APC and T-cell • CD80/86 (aka B7) on APC with CD28 on T-cell • “reinforces” and strengthens immune signal transduced through CD3 complex • Combined action of signals 1 & 2 activate important intracellular pathways N Engl J Med 2004;351:2715-29.

  10. Combined action of signals 1 & 2 activate important intracellular pathways • Calcium-calcineurin pathway • RAS-MAP kinase pathway • Nulcear factor-κB pathway • Leads to • production of IL-2 and other growth promoting cytokines • Expression of IL-2 receptor (CD25) N Engl J Med 2004;351:2715-29.

  11. Signal 3: Mammalian target ofrapamycin (mTOR) activation • IL-2 produced binds to newly activated IL-2 receptor (CD25) • Binding activates mTOR • mTOR activation triggers cell cycle • Lymphocyte proliferation • Results in large numbers of effector T-cells N Engl J Med 2004;351:2715-29.

  12. Result of effector T-cells • Effector T-cells targeted at donor antigen infiltrate graft • Interstitial and/or perivascular infiltration • Cascade of activation of macrophages, B-cells, plasma cells • Resultant cell lysis • Severe – edema, hemorrhage, vasculitis

  13. Three Signal Model of T cell Activation[adapted from Sing-Leung 2001] Antigen Presenting Cell MHC II B7 Antigen Interleukin-2 CD45 CD4CD3CD28 Interleukin-2 receptor T Lymphocyte Target lymphocyte Signal 1 Signal 2 Signal 3 TCR Purine Synthesis Calcineurin Pathway TOR Pathway Cytokine gene nucleus Cell Cycle

  14. Sites of Action of Immunosuppressive Medications[adapted from Sing-Leung 2001] Antigen Presenting Cell Steroids MHC II B7 Interleukin-2 CD45CD4CD3CD28 Interleukin-2 receptor T Lymphocyte Target lymphocyte Signal 1 Signal 2 Signal 3 ATG Anti-IL-2R OKT3 Belatacept TCR Purine Synthesis Sirolimus Cyclosporine & Tacrolimus TOR Pathway Calcineurin Pathway MMF Steroids Cytokine gene nucleus Cell Cycle

  15. Individual Immunosuppressive Drugs and Sites of Action in the Three-Signal Model N Engl J Med 2004;351:2715-2729

  16. Target Antigens

  17. Immunosuppressant drugs • Calcineurin inhibitors • Ciclosporin A • Tacrolimus • Anti-metabolites • Azathioprine • Mycophenolates • Leflunomide? • m-TOR inhibitors • Sirolimus • Everolimus

  18. Newer antibody drugs • Alemtuzumab • Rituximab • IL-2 receptor ‘mabs’ • Basiliximab • Daclizumab

  19. CNI’s:Tacrolimus and Cyclosporine • Major breakthrough in modern transplantation • Lead to significant improvements in outcome • “Backbone” of most IMS protocols • Similar mechanisms of action • Differ in structure and receptor interactions Transplant Proc 2004;36:25S-32S. Am J Kidney Dis 2006;47:S3-21.

  20. Calcineurin inhibitors (CNIs) : Mechanism of action • Forms complex with cytosolic proteins (aka immunophilins) • CSA = cyclophilin • Tacrolimus = FKBP-12 (FK-binding protein) • ↑ affinity and binding of immunophilin-drug complex to calcineurin • Inhibits of transcription of IL-2, other cytokines • ↓ T-cell activation & proliferation Transplant Proc 2004;36:25S-32S. Circulation 2004;110:3858-65.

  21. Calcineurin inhibitors (CNIs) • Ciclosporin A (CyA) binds to intracellular protein, cyclophilin • only active once bound • Tacrolimus (FK506) binds to intracellular protein, FKBP-12 • only active once bound

  22. The fungus Tolypocladium inflatum • Fungal source of CyA • Hydrophobic cyclic endecapeptide

  23. Scanning electron micrograph of Streptomyces tsukubaensis • Bacterial source of tacrolimus • Sirolimus from Streptomyces hygroscopicus & very similar structure

  24. Basic mode of action • (Drug + immunophilin) inhibits calcineurin • Prevents dephosphorylation (activation) of NF-Act T-cell • factors which stimulate cytokine (i.e. IL-2/IFN-) gene transcription • Net result: impaired IL-2 production • ‘reversible inhibition of T-cell activation, proliferation & clonal expansion’ • Stops cell cycle at G0-G1 stage

  25. Ciclosporin A & tacrolimus share a mechanism of action and metabolic route • Never given together (additive nephrotoxicity) • Tac interacting with CyA? • 12-24hr gap only if converting • Differences include ADR’s & efficacy

  26. Ciclosporin • Oral absorption • Large inter & intra-patient variability • Food & juices • IV dose & administration • Distribution – extensive (not dialysed) • Metabolism • CYP450 3A4 with adult half-life 5-18 hours • Shorter in children • Steady state 2-3 days after change of dose

  27. Tacrolimus • Absorption • Fatty food decreases rate & extent • >80% distributes into erythrocytes • Whole blood trough levels • Remainder 99% protein bound • CYP450 3A4 metabolism • Adult half-life approx 9-12 hours • Clearance faster in <6yrs

  28. Metabolic interactions on CNI & m-TOR inhibitor levels

  29. Typical CNI doses target levels

  30. Anti-metabolites • Only purine anti-metabolites routinely used • 1) Azathioprine • 2) Two mycophenolate presentations • mofetil • sodium EC

  31. Azathioprine • Guanine anti-metabolite • rapidly converted  6-mercaptopurine  thioguanine nucleotides • Disrupts synthesis of developing cellular DNA & RNA strands & so prevent mitosis • ‘Prevents early stages of activated T & B-cell proliferation’

  32. One metabolic route involves thiopurine methyltransferase (TPMT). • Absent in 1 in 300 • Toxicity • Final metabolism to inactive 6-thiouric acid • Via xanthine oxidase • Quarter dose in combination with allopurinol • Usual starting dose 1-2mg/Kg • Can use 50% dose if giving iv

  33. Maintenance immunosuppression over first year after transplantation (1994-2003). (2005 OPTN/SRTR Annual report)

  34. Mycophenolic acid precursors • Isolated in 1896 from Penicillium spp. • mofetil ester rapidly cleaved  active mycophenolic acid (MPA)

  35. 1 enzyme is rate limiting step in lymphocyte de novo purine biosynthesis • Inosine Mono-Phosphate DeHydrogenase • Mycophenolic acid non-competitively inhibits IMPDH • Prevents production of Guanosine triphosphate (GTP) • Impairs production of DNA limiting lymphocyte proliferation • T & B-lymphocytes preferentially use this pathway for purine production. • Other cell lines have salvage pathways.

  36. Molar equivalent doses: • 1gram MMF = 720mg MPS EC • Paed MMF dose with ciclosporin 600mg/M2 bd • MMF dose with tacrolimus = less (50-25%) • MPA glucuronide undergoes entero-hepatic recirculation • Second peak maintains levels • ciclosporin inhibits this recirculation • MMF injection available if necessary • Same dose iv as oral • Requires aseptic manipulation

  37. Interactions • Magnesium & aluminium (antacids) • Reduced absorption • Cholestyramine • Reduced entero-hepatic recirculation • (Val) aciclovir • Competes for tubular secretion with MPAG • Modest effect • +12% MPAG AUC & +20% aciclovir AUC

  38. Pros & cons of mycophenolate • Reduced incidence of ACR c.f. placebo or azathioprine with Sandimmune & steroid • Lower incidence CAN c.f. azathioprine • Reduced interstitial fibrosis? • Much more expensive than azathioprine • Higher incidence of GI ADR - strategies • diarrhoea 12.7 – 31.5% • abdominal pain 11.5 – 26% • nausea 4.2 – 14% and vomiting 2.4 – 12%. • Higher incidence of anaemia (15%)

  39. Sirolimus • Another macrocyclic antibiotic • Immunophilin binder (like CyA & FK506) • also bind ubiquitous protein, FKBP-12 • Does not inhibit cytokine (i.e. IL-2) gene transcription • Complex inhibits m-TOR • Inhibits multiple biological steps • e.g. activation of p70S6 kinase • Prevents IL-2-mediated signal transduction to cell nucleus • Cell cycle arrest at G1-S phase • Also inhibits tumour cell & smooth muscle cell proliferation (CAN)

  40. Absorption is poor • Food also affects rate & extent • Consistency • Widely distributed into tissues • CYP450 3A4 & P-glycoprotein metabolism • Adult half-life long (57-63 hours) • Clearance slightly higher in <11yrs cf 12-18yrs • Levels 4-12ng/mL, no more frequently than every fortnight.

  41. Adverse effect profile dissimilar to CNIs • Not nephrotoxic • Wound healing delay & fascial dehiscence • lymphocele formation • Mouth ulceration – transient? Topical steroid • Acne and pilosebaceous rash - doxycycline • Peripheral & angioedema >10% - withdrawal • Dose related mixed hyperlipidaema - statins • Anaemia & thrombocytopaenia • Arthralgias – dose reduction or withdrawal • Interstitial lung disease - withdrawal

  42. Adverse events leading to discontinuation Transplantation 2003: 76; 364-370.

  43. Use of sirolimus • Licensed for use with ciclosporin A for 1st 3 months only in adult renal transplant • Rarely used in this way • Where to position sirolimus? • Replace CNI or replace anti-metabolite • Appears to offer better GFR (graft survival?) than CNI maintenance. • Skin cancers??

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