A clinical research consortium sponsored by NIAID and JDRF
Kawai T, Sachs DH, Spitzer T, Sykes M, Tolkoff-Rubin N, Delmonico F, Saidman S, Shaffer J, Dey B, McAfee S, Ko D, Wong W, Williams W, Goes N, Hertl M, Smith RN, Colvin RB, Cosimi AB
Massachusetts General Hospital, Harvard Medical School, Boston, MA
Aims : To induce allograft tolerance through mixed chimerism, a non-myeloablative conditioning regimen was administered to three recipients of HLA haploidentical kidney transplants.
Methods: The patients received combined kidney and bone marrow transplantation (KBMT) 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 with a previous history of rejected kidney transplantation underwent KBMT from her mother. She developed mixed chimerism (T cell 5.2%, Granulo 90.6%) on day 7 with no evidence of GVHD. Chimerism became undetectable by day 14 but there was no evidence of renal allograft rejection on sequential biopsies. CyA was slowly tapered and finally discontinued by day 240. Her renal function remains stable, with serum creatinine of 1.3 mg/dl on day 500. Protocol renal biopsy at 1 year was normal and specific hyporesponsiveness was demonstrated in MLR and CML. No anti-donor alloantibody ( ADA) has been detected. Case 2: A 22 y.o. man with renal failure secondary to membranoproliferative glomerulonephritis underwent KBMT from his father. He developed similar transient chimerism (T cell 3%, Granulo 60%) on day 7. He subsequently developed acute tubular necrosis, believed to be secondary to engraftment syndrome, but allograft function then gradually recovered after steroid pulse therapy. On day 45, a kidney biopsy prompted by a moderate creatinine elevation showed C4d staining, suggesting possible humoral rejection. Although no serum ADA was detected, he was treated for humoral rejection and CyA was switched to Prograf , Mycofenolate mofetil and prednisone. Renal allograft function stabilized thereafter and creatinine recovered to 2.0 mg/dl by day 60. Prednisone and Mycophenolate mofetil were discontinued by day 200 and Prograf has been tapered to 1mg/day (trough <2 ng/dl) . Current creatinine is 1.8 mg/dl on day 282. ADA remains negative with specific hyporesponsiveness in MLR and CML. Kidney biopsies on days 87 and 265 revealed no rejection and were negative for C4d. Case 3: A 39 y.o. man with renal failure due to polycystic kidney disease underwent KBMT from his sister. He also developed transient chimerism (T cell 15-40%, Granulo 75-85%) on days 5 and 7. However, his renal allograft function rapidly deteriorated on day 10 due to humoral rejection with positive ADA. He was immediately treated intensively for humoral rejection, but he currently has compromised allograft function, although not yet requiring dialysis.
Conclusion: Induction of allograft tolerance via mixed chimerism can be achieved in recipients of HLA mismatched kidneys, although additions to the conditioning regimen to suppress engraftment syndrome and avoid early humoral responses may be indicated.
