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1 Immunosuppression en transplantation d'organes solides Jean Tchervenkov MD (Marcelo Cantarovich MD)
2 Immunosuppressive protocols Induction therapy During the first 1-2 weeks post-tx Controversy about its use Polyclonal antibodies ATG, ALG Monoclonal l antibodies OKT3 (less frequently used) IL-2 receptor mab (more frequently used) Campath-1H (more recent) CTLA4Ig, LEAY29 (more recent)
3 Immunosuppressive protocols Corticosteroids Maintenance therapy Avoidance Early withdrawal (1 week, <3 months) Late withdrawal No withdrawal Calcineurin inhibitors Cyclosporine Tacrolimus (FK 506) Avoidance Minimization Discontinuation Anti-metabolites or Inhibitors of nucleotide synthesis Azathioprine Mycophenolate mofetil EC-MPA mtor (Target of rapamycin) Inhibitors Rapamycin derivative (Everolimus) Rapamycin (Sirolimus) mtor
4 Immunosuppressive Glucocorticoids therapies Small-molecule molecule drugs Protein drugs
5 Corticosteroids Methylprednisolone, l Prednisone Inhibit IL-1 expression and down- regulates inflammatory cascade Non specific immunosuppressive agent
6 Corticosteroids Side-effectseffects muscular atrophy osteoporosis hypertension weight gain moonface hyperglycemia hyperlipidemia cataracts acne mood swings gastritis growth retardation
7 Small-molecule molecule drugs Immunophilin-binding drugs Calcineurin inhibitors Cyclophilin-binding drugs Cyclosporine, ISA-247 FKBP12-binding drugs Tacrolimus, modified release tacrolimus Target-of of-rapamycin inhibitors Sirolimus and everolimus
8 Calcineurin inhibitors Pharmacology Cyclosporine C-max: hr Less dependent of food than Sandimmune Half-life life 8-27 hr Bioavailability 65-77% Distribution Plasma 33-47% 90% bound to proteins Lymphocytes 4-9% RBC 41-58% Metabolism Cytochrome P450 3A Hepatic >90%, 6% renal 15 metabolites Tacrolimus C-max: hr Food decreases absorption Half-life life hr Bioavailability 17-34% Distribution 99% bound to proteins Metabolism Cytochrome P450 3A Mainly hepatic Racial differences in polymorphic expression of CYP3A5 and p-glycoprotein (MDR1) may explain observed interracial variability in oral bioavailability
9 Cyclosporine (CsA) Mecanism of action Inhibition of (mainly) IL-2 gene transcription by complexing pe cac calcineurin Reduces T-Cell activation Dose PO: 2-15 mg/kg/day BID IV: 1 mg/kg/day g (continuous infusion) Therapeutic dose monitoring Trough level vs. C2 monitoring
10 Nephrotoxicity Neurotoxicity (tremor, seizures) Hirsutism Gingivitis Hypertension Hyperglycemia CsA Side-effectseffects Hepatotoxicity Dyslipidemia Malignancies Electrolyte disorders Hypo Mg ++ Hyper K + Hyperuricemia
11 CsA* Drug interactions Metabolism through CYP3A4 CsA levels (CYP3A4 inhibitors) Antibiotics Macrolides (Erythromycin, Clarithromycine) Azithromycin does not appear to inhibit CYP3A4 Azoles (Fluconazole, Itraconazole, Ketoconazole) Cardiovascular diltiazem, verapamil, nicardipine, amiodarone Grapefruit juice *Idem tacrolimus and Rapa
12 CsA* Drug interactions CsA levels (CYP3A4 inducers) Anticonvulsants Carbamazepine Phenytoin Phenobarbital Antibiotics Rifampicin Isoniazid *Idem tacrolimus and Rapa
13 CsA Drug interactions Effect of CsA on other drugs digoxin level statin level Risk of myopathy/rhabdomyolysis y y y gingival hyperplasia with nifedipine and phenytoin
14 CsA Drug interactions nephrotoxicity Amphotericin B Foscarnet Aminoglycosides NSAIDs Septra
15 Neoral Dosing Close monitoring i is required Narrow therapeutic window
16 Tacrolimus Mechanism of Action 100-fold more potent in vitro than CsA and 10- fold more potent in vivo in inhibiting T-cell activation Inhibits CN phosphatase p and intracellular signal transduction (IL-2) and T-cell proliferation Highly lipophilic p bioavailability: 5% to 67% Food absorption
17 Dose Tacrolimus PO: 0.05 to 0.30 mg/kg/day (bid) iv: avoid use because of side- effects Blood trough levels l
18 Tacrolimus Side-effectseffects incidence vs. CsA Hirsutism Gingival hyperplasia Hypercholesterolemia incidence vs. CsA Diarrhea Hyperglycemia Hyper K +, hypo Mg ++ Allopecia Neurotoxicity
19 Small-molecule molecule drugs Immunophilin-binding drugs Calcineurin inhibitors Cyclophilin-binding drugs Cyclosporine, ISA-247 FKBP12-binding drugs Tacrolimus, modified release tacrolimus Target-of-rapamycin inhibitors Sirolimus and everolimus
20 Target-of of-rapamycin Inhibitors Binding to FKBP12 Inhibit the target of rapamycin Blocks signal 3 by preventing cytokine receptors from activating the cell cycle Does not inhibit calcineurin
21 Dosage Sirolimus De novo: 10 mg PO x 1, then 5 mg po QD Blood trough levels (10-20 ng/ml) Long-term: 5 mg PO x 1, then 2 mg QD Blood trough levels (6-12 ng/ml) Everolimus mg PO BID Blood trough levels (3-8 ng/ml)
22 Side-effects effects Tg, LDL GI and BM toxicity PO 4-, K + Diabetogenic effect Acne, skin rash, oral ulcers Delayed wound healing Delayed recovery from ATN Proteinuria Pneumonitis Edema Lymphedema
23 Drug interactions Same as CsA / tacrolimus CYP3A4 MPA levels (4.4 fold vs. CsA) CsA + sirolimus (phramacodynamic interaction) Give sirolimus 4-hr post-csa CsA dose
24 Additional effects Sirolimus and everolimus may reduce the incidence of CMV disease Increased incidence of CNI nephrotoxicity Anti-neoplastic neoplastic effect Decrease incidence of CAN
25 Small-molecule molecule drugs Inhibitors of nucleotide synthesis Purine synthesis (IMPDH) inhibitors Mycophenolate mofetil (MMF) Enteric coated mycophenolic acid (MPA) Mizoribine Pyrimidine synthesis (DHODH) inhibitors Leflunomide FK 778
26 Inosine Monophosphate Dehydrogenase Inhibitors MMF: Prodrug, metabolized in liver to MPA MMF + CsA was superior to azathioprine in preventing acute rejection MMF + CNI improved patient and graft survival MMF Inhibits smooth muscle cell proliferation Enteric-coated coated MPA: alternative to MMF
27 Dosage MMF: 2-3 g/day in two doses Enteric-coated MPA: 720 mg BID
28 MMF: Mechanism of Action MPA inhibits proliferation & differentiation of lymphocytes by blocking specific purine synthesis pathway Mycophenolate in vivo MP GTP Mofetil hydrolysis Anucleic acids De Novo Pathway PRPP inosine monophosphate xanthine monophosphate guanosine monophosphate Salvage Pathway hypoxanthine xanthine guanine
29 MMF Side-effectseffects Dose-dependant GI (nausea, vomiting, diarrhea) BM toxicity
30 MMF Drug interactions MMF absorption Cholestyramine Antacids (Mg, Al) MMF level Probenecid (inhibits renal excretion) Salicylates (increase free fraction)
31 Small-molecule molecule drugs Inhibitors of nucleotide synthesis Purine synthesis (IMPDH) inhibitors Mycophenolate mofetil Enteric coated mycophenolic acid Mizoribine Pyrimidine synthesis (DHODH) inhibitors Leflunomide FK 778
32 Dihydroorotate Dehydrogenase Inhibitors DHOD: Key enzyme in pyrimidine synthesis Leflunomide is approved for rheumatoid arthritis but not widely used in Tx FK778 (active metabolite of leflunomide), in phase 2 trials May have activity against polyomavirus Lower incidence of GI side-effects effects than MMF Anemia
33 Small-molecule molecule drugs Antimetabolites Azathioprine Sphingosine 1-phosphate-receptor antagonists FTY 720
34 Azathioprine (Imuran) Nonspecific inhibitor of cell proliferation Pro-drug metabolized to 6-MP Less specific than MMF on purine synthesis pathway Used in combination with CsA or FK mg/kg/day (PO, die) Available iv
35 Azathioprine Side-effectseffects BM toxicity Hepatotoxicity (rare) GI (rare) Pancreatitis (rare) Interaction with allopurinol Same metabolic pathway Aza dose by 1/3 to 1/4
36 Immunosuppressive Glucocorticoids therapies Small-molecule molecule drugs Protein drugs
37 Protein drugs Depleting antibodies (T-cells, B-cells, both) Polyclonal antibodies (horse or rabbit ATG) Monoclonal antibodies Mouse anti-cd3 mab (muromomab-cd3) Humanized anti-cd52 mab (alemtuzamab) B-cell-depleting anti-cd20 mab(rituximab)
38 Anti-lymphocyte and anti-thymocyte thymocyte globulins Used as immunosuppressive agents since late 1960s Differences among ATGs and ALGs Animal species Antigen preparations Immunization protocols Purification (serum vs. globulin) Quality control o procedures es Batch consistency
39 Thymoglobulin CD3/TCR, CD2, CD4, CD5, CD6, CD8, CD27, CD28, CD96, CDw150, CD Target Antigens T lymphocytes Granulocytes Integrins, MHC I... Other shared epitopes Red blood cells Platelets TCR = T-cell receptor; MHC = major histocompatibility complex
40 ATG Dose and indication 1.5 mg/kg/dose (1 vial = 25 mg) Cumulative dose 6 mg/kg Prophylaxis and treatment of acute rejection
41 ATG Side-effectseffects Peripheral vs. central vein Anaphylaxis Cytokine release syndrome Fever, chills, shivering, dyspnea, nausea, vomiting, diarrhea, aseptic meningitis BM toxicity Serum sickness Infections Viral (Herpes, EBV, CMV) PTLD
42 Protein drugs Depleting antibodies (T-cells, B-cells, both) Polyclonal antibodies (horse or rabbit ATG) Monoclonal antibodies Mouse anti-cd3 mab (muromomab-cd3) Humanized anti-cd52 mab (alemtuzamab) B-cell-depleting anti-cd20 mab (rituximab)
43 OKT3 Side-effectseffects Side-effects effects post-injection Anaphylactic shock Cytokine release syndrome Infections Viral (Herpes, EBV, CMV) PTLD
44 Campath-1H ( 1H (Alemtuzumab) Humanized mab against CD52 Massive lymphocyte depletion Approved for B-cell CLL Not approved for Tx immunosuppression?induction of tolerance (not confirmed) First-dose reaction, neutropenia, anemia Rarely pancytopenia and autoimmunity Unknown risks of infections and cancer
45 Rituximab Anti-CD CD20 mab, depletes most B cells Approved for treating refractory non- Hodgkin's B-cell lymphomas (PTLD) Off-label use + plasmapheresis + IVIg to treat antibody-mediated acute rejection Plasma cells are usually CD20 (-), but many are short-lived and require replacement from CD20 (+) precursors
46 Protein drugs Non depleting antibodies and fusion proteins Humanized or chimeric anti-cd25 mab Basiliximab, Daclizumab Fusion protein with natural binding properties CTLA-4-Ig LEA29Y
47 Basiliximab i / Daclizumab Dose, indication & administration Prophylaxis of rejection Basiliximab 20 mg IV Day#0 + Day#4 Daclizumab 11 mg/kg q. 2 wks x 5 Off Off-label 22 mg/kg POD#0 22 mg/kg POD#0 and 1 mg/kg POD 15
48 Basiliximab / Daclizumab Side-effectseffects Excellent tolerance Hypersensitivity reaction (<1/1000) No cytokine-release syndrome
49 Protein drugs Non depleting antibodies and fusion proteins Humanized or chimeric anti-cd25 mab Basiliximab, Daclizumab Fusion protein with natural binding properties CTLA-4-Ig LEA29Y
50 Targeting cell-surface receptors CD28/B7 blockade CD28 binds to CD80/CD86 (B7.1 and B7.2) CTLA-4Ig blocks CTLA-4 (binds to CD80/CD86) It requires high doses Induction of tolerance in murine allograft and xenograft models LEA29Y (2 nd generation agent is under investigation) h1f1 and h3d1 (humanized mabs vs. CD80/CD86) ICOS/B7RP-1 ICOS (inducible costimulator) binds to B7RP-1 (member of the B7 family) CD40/CD40L CD11a/LFA-1 VLA4/VCAM-1
51 LEA29Y ( (Belatacept) Second-generation cytotoxic-t-lymphocyte lymphocyte y associated antigen 4 (CTLA-4) Ig Fusion protein that combines CTLA-4 (binds to CD80 and CD86) with the Fc portion of IgG Phase 2trial in renal Tx pts on MMF, Pred and anti-cd CD25 antibody Repeated infusions of LEA29Y over 6-mo follow- up was similar to CsA in preventing rejection with lower incidence of IFTA
52 New Drugs Potential targets for small-molecule molecule drugs Tyrosine kinases (Janus kinase 3 (JAK3) inhibitors), protein kinase C, MAP kinases such as Jun N- terminal kinase, phosphoinositide-3-kinase, and chemokine receptors. Potential targets for protein drugs include many membrane proteins.
53 Other perspectives Minimize or eliminate calcineurin inhibitors Minimize or eliminate steroids Rescue after refractory acute rejection Individualize immunosuppression Immune monitoring i Pharmacogenomics Minimize or eliminate chronic graft failure Tolerance Xenotransplantation
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