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TRANSPLANTATION PHYSIOLOGY

TRANSPLANTATION PHYSIOLOGY. Part 4 of 4. Robert L. Madden MD, FACS Associate Professor of Surgery Tufts University School of Medicine Baystate Medical Center Springfield, MA. Which one of the following statements is false. Graft-versus-host-disease (GVHD) … :

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TRANSPLANTATION PHYSIOLOGY

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  1. TRANSPLANTATIONPHYSIOLOGY Part 4 of 4 Robert L. Madden MD, FACS Associate Professor of Surgery Tufts University School of Medicine Baystate Medical Center Springfield, MA

  2. Which one of the following statements is false. Graft-versus-host-disease (GVHD) … : a.is injury in a transplant recipient caused by donor T cells. b.can occur with bone marrow and small intestinal transplantation. c.presents acutely with skin rash, jaundice, and diarrhea.

  3. d.if severe, can be fatal. e.is best treated with a decrease in immunosuppression to allow a rebound of the recipient’s immune activity.

  4. d.if severe, can be fatal. e.is best treated with a decrease in immunosuppression to allow a rebound of the recipient’s immune activity.

  5. C.Graft-versus-host disease (GVHD) 1.Recipient injury caused by donor T cells (recognize alloAg of recipient) that were transferred during transplant procedure a.bone marrow transplantation b.small intestine and lung transplantation 2.Acute GVHD a.necrosis of epithelial cells in skin, liver (bile ducts), and GI tract b.clinical symptoms - skin rash, jaundice, diarrhea c.if severe, can be fatal

  6. 3.Chronic GVHD a.fibrosis of skin, liver, GI tract and lungs without necrosis b.if severe, can lead to complete dysfunction of involved organ and death 4.Donor NK cells may be responsible for recipient epithelial cell damage 5.Acute and chronic GVHD treated with intense immunosuppressive therapy - often more resistant to treatment than allograft rejection (possibly because of NK cell involvement)

  7. PREVENTION OF ALLOGRAFT REJECTION A.Prevention strategies vary with transplant center B.Two main approaches are utilized: 1.Render the allograft less immunogenic a.elimination of MHC class II bearing cells in allograft i.allograft passenger leukocyte depletion prior to transplan- tation ii.prolongs allograft survival in animal models

  8. iii.not clinically applicable because human endothelial cells express class II Ags b.minimization of alloAg differences between donor and recipient i.assure ABO compatibility ii.HLA matching used in donor selection 2.Suppression of recipient immune system - immunosuppression a.mainstay of successful clinical transplantation

  9. The mechanisms of action of cyclosporine and tacrolimus are similar in that they both … : a.inhibit IL-2 transcription. b.inhibit IL-1, IL-6 and TNF synthesis. c.inhibit inosine monophosphate dehydro- genase and thereby block de-novo purine synthesis d.bind to the CD3 portion of the TCR and cause depletion of CD3+ T cells. e.become incorporated into DNA and block lymphocyte proliferation.

  10. The mechanisms of action of cyclosporine and tacrolimus are similar in that they both … : a.inhibit IL-2 transcription. b.inhibit IL-1, IL-6 and TNF synthesis. c.inhibit inosine monophosphate dehydro- genase and thereby block de-novo purine synthesis d.bind to the CD3 portion of the TCR and cause depletion of CD3+ T cells. e.become incorporated into DNA and block lymphocyte proliferation.

  11. b.corticosteroids (methylprednisolone, prednisone, etc.) i.multiple anti-inflammatory actions ii.block cytokine production iii.inhibit IL-1, IL-6 and TNF synthesis iv.dose: rapid taper after transplant - low maintenance dose v.high dose - T cell lysis

  12. vi.side effects: a.increased infection susceptibility b.impaired healing c.weight gain d.diabetagenic e.fluid retention f.avascular hip necrosis g.cataract formation h.peptic ulcer disease i.exacerbate hypertension j.etc.

  13. c.azathioprine (Imuran) i.purine analog/antimetabolite ii.inhibits lymphocyte proliferation iii.dose: 1-2 mg/kg/day iv.side effects: a.bone marrow suppression b.decreased resistance to infection/tumor c.hepatoxicity (rare)

  14. d.cyclosporine (Sandimmune, Neoral) (CsA) i.fungal metabolite ii.binds to cyclophilin in cytosol iii.complex binds to calcineurin - blocks NFAT (transcription factor) activation iv.inhibits IL-2 transcription v.dose: bid dosing based on blood levels

  15. vi.side effects: a.nephrotoxicity b.decreased resistance to infection/tumor c.exacerbates hypertension d.diabetagenic e.hepatotoxicity f.tremor g.hirsutism h.gingival hyperplasia vii.expensive

  16. e.tacrolimus (FK506, Prograf) (Tac) i.macrolide antibiotic ii.binds to FK binding protein in cytosol iii.complex binds to calcineurin - blocks NFAT iv.inhibits IL-2 transcription v.dose: bid dosing based on blood levels

  17. vi.side effects: a.similar side effect profile to CsA b.more neurotoxic and diabetagenic than CsA c.no hirsutism or gingival hyperplasia vii.expensive

  18. f.mycophenolate mofetil (RS-61443, CellCept) (MMF) i.ethyl ester of mycophenolic acid ii.metabolized to mycophenolic acid iii.inhibits inosine monophosphate dehydrogenase iv.blocks de-novo purine synthesis v.lymphocytes rely on de-novo pathway (most other cells have good salvage pathway for purine synthesis) vi.dose: bid based on levels

  19. vii.side effects: a.gastrointestinal distress b.rare bone marrow suppression c.decreased resistance to infection/tumor viii.expensive

  20. g.rapamycin (sirolimus, Rapamune) i.macrolide antibiotic ii.binds to FK binding protein in cytosol iii.modulates the activity of mTOR (mammalian Target of Rapamycin) iv.prevents IL-2 driven cell proliferation v.inhibits T and B cell proliferation

  21. vi.side effects: a.hyperlipidemia b.bone marrow suppression; anemia c.decreased resistance to infection/tumor d.rash e.pneumonitis f.GI distress viii.expensive

  22. 3.Maintenance immunosuppression a.protocols vary by transplant center b.most US centers use “triple” or “dual” therapy c.triple - CsA or Tac + azathioprine or MMF or sirolimus + steroids d.dual - CsA or Tac + steroids e.rationale similar to chemotherapy rationale - use of multiple drug regimen reduces side effects as opposed to high-dose monotherapy f.recipients must be compliant with immunosuppressive regimens for life of allograft

  23. 4.Induction immunosuppression (“sequential”) a.additional immunosuppressive medication (given in addition to maintenance immunosuppression) started at or immediately before the transplant operation and continued for only 1-3 weeks b.usually monoclonal or polyclonal Ab preparation

  24. c.use varies with transplant center i.some always use induction/some never ii.some use selective induction (eg., for delayed or poor initial allograft function, and/or for highly sensitized recipients) d.polyclonal antilymphocyte serum i.ALS, ATGAM, RATS, Thymglobulin ii.made in horse, goat, rabbit

  25. iii.mechanism of action not completely understood - cause T cell depletion iv.dose: given daily x 5-15 days v.side effects: a.anaphylaxis b.fever c.serum sickness d.thrombocytopenia e.local phlebitis f.bone marrow suppression vi.expensive - $500 - $1000/dose

  26. e.anti-CD3 Ab (OKT-3) i.monoclonal murine Ab (hybridoma) ii.specific for CD3 molecule on T cells (part of TCR) iii.mechanism of action not completely understood - causes T cell (CD3+) cell depletion a.T cell lysis b.T cell margination c.T cell receptor blockade d.T cell loss of TCR iv.dose: 5 mg/day x 10-14 days

  27. v.side effects: a.anaphylaxis b.activating Ab - massive cytokine release (“cytokine release syndrome”) i.pulmonary edema ii.fever iii.nausea/vomit iv.headache v.tremor vi.malaise vii.diarrhea c.decreased resistance to infection/tumor vi.expensive - $300 - $500/dose

  28. f.anti-CD25 Ab (anti-Tac, anti-IL-2R, Simulect, Zenapax) i.monoclonal Abs specific for IL-2R ii.inhibit T cell activation by blocking IL-2 binding iii.dose: varies with manufacturer (usually given for 2-5 doses after transplant) iv.side effects: minimal v.expensive - $1000 - $2000/dose

  29. TREATMENT OF ALLOGRAFT REJECTION A.Treatment strategies vary with transplant center B.Critical to make proper diagnosis 1.Many clinical entities can mimic rejection 2.Inappropriate use of anti-rejection therapy can cause significant morbidity and/or mortality 3.No highly sensitive/specific diagnostic tests) 4.Biopsy is often needed to confirm a diagnosis of rejection (but still not 100% accurate)

  30. True or false: Most US renal transplant centers initiate treatment of an acute rejection episode with a combination of allograft irradiation and high dose tacrolimus.

  31. True or false: Most US renal transplant centers initiate treatment of an acute rejection episode with a combination of allograft irradiation and high dose tacrolimus.

  32. C.Treatment options: 1.High dose steroids a.250-1000 mg/day methylpredisolone (some centers use oral) b.usually given for 3-5 days c.reverses (stops) approx. 75% of rejection episodes d.if inadequate response, change to alternate treatment

  33. 2.Antibody preparation a.OKT-3 or Thymoglobulin used most commonly b.very potent anti-rejection therapies c.reverses 75-90% of rejection episodes 3.Plasmapharesis a.removes Abs from blood b.immunosuppressive c.often used in conjuction with IVIg for humoral rejection d.exact indications are not well-defined

  34. 4.“Rescue” therapy a.used when other anti-rejection therapies have failed i.high dose tacrolimus ii.mycophenolate mofetil 5.Allograft irradiation a.most commonly used as a “last ditch” effort b.dose: 100-150 cGy/day x 5 days c.efficacy not well-known

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