Presented at:
American Transplant Congress, Boston, MA,
May 18, 2004
Combined kidney and bone marrow transplantation for induction of mixed chimerism and renal allograft tolerance in HLA mismatched transplantation
Kawai T, Sachs DH, Spitzer T, Sykes M, Tolkoff-Rubin N, Delmonico F, Saidman S, Shaffer J, Dey B, McAfee S, Williams W, Ko D, Hertl M, Goes N, Wong W, Colvin RB, Cosimi AB.
Transplant Unit, Massachusetts General Hospital, Boston, MA; Transplant Biology Research Center, Massachusetts General Hospital, Charlestown, MA; Hematology, Massachusetts General Hospital, Boston, MA; Pathology, Massachusetts General Hospital, Boston, MA
Purpose: To induce allograft tolerance through mixed chimerism, a non-myeloablative conditioning regimen was tested in three recipients of HLA mismatched kidney transplants.
Methods: Three patients received combined kidney and bone marrow transplantation from HLA haploidentical donors following conditioning with cyclophosphamide (60mg/kg x2), thymic irradiation (7 Gy), anti-CD2 mAb and a limited course of cyclosporine (CyA).
Results:
Case 1; A 22 y.o. woman developed mixed chimerism (T cell 5.2%, Granulo 90.6%) on day 7 with no GVHD. Chimerism became undetectable by day 14 but there was no evidence of rejection on sequential biopsies and her immunosuppressive medications were slowly tapered and finally discontinued by day 240. Her renal function remained stable, with serum creatinine of 1.2 mg/dl on day 440. Normal biopsy at 1 year was obtained and specific hyporesponsiveness has been demonstrated in MLR and CML.
Case 2: A 22 y.o. man developed similar transient chimerism (T cell 3%, Granulo 60%) on day 7. After day 10, he developed acute tubular necrosis, believed to be secondary to engraftment syndrome, but the kidney allograft gradually recovered after steroid pulse therapy. On day 45, a kidney biopsy prompted by a moderate creatinine elevation suggested humoral rejection with positive C4d staining. Although no anti-donor alloantibody was detected in his serum, he was treated for humoral rejection and CyA was switched to Prograf, resulting in improved allograft function (creat 1.8) on day 171. His immunosuppression has been steadily tapered to current level of Prograf (trough 4 ng/dl) and prednisone (2.5 mg/day). A kidney biopsy on day 87 revealed no rejection and specific hyporesponsiveness was demonstrated in vitro.
Case 3: A 39 y.o. man, too recently treated for complete evaluation, developed evidence of humoral rejection 10 days post transplantation. He currently has compromised allograft function, not requiring institution of dialysis. Further results will be available at the time of presentation.
Conclusion: Induction of allograft tolerance via mixed chimerism appears to be achievable in recipients of HLA mismatched kidneys, but may require intensified suppression of humoral responses.