A clinical research consortium sponsored by NIAID and JDRF
Kawai T, Spitzer T, Tolkoff-Rubin N, Saidman S, Dey B, Goes N, Ko D, Hertl M, Cotter P, Wong W, Colvin R, Sykes M, Cosimi AB, Sachs D, WilliamsW
Massachusetts General Hospital, Boston, MA.
BACKGROUND:During the past half century, remarkable progress has been made in the field of organ transplantation, especially in the control of acute rejection by conventional immunosuppressive agents. Unfortunately, this has not significantly altered longer-term results mainly due to chronic rejection but also because of non-compliance with immunosuppressive medications and the side effects of these agents themselves. Therefore, the induction of donor-specific tolerance is currently one of the most important goals of organ or cell transplantation. Based on studies in mice, swine and non-human primates, we developed a clinically applicable non-myeloablative preparative regimen for induction of mixed hematopoietic chimerism and renal allograft tolerance, which has now been administered to five recipients of HLA mismatched kidney transplants.
METHODS: Five subjects with ESRD received combined bone marrow and kidney transplantation from one-haplotype-mismatched, related donors. The preparative regimen consisted of cyclophosphamide (60mg/kg X 2), thymic irradiation, anti-CD2 mAb and a 9-14 months course of a calcineurin inhibitor. Two subjects also received two doses of anti-CD20 mAb prior to transplant.
RESULTS: All five recipients developed transient mixed chimerism. Immunosuppression was tapered slowly in the first subject and was discontinued on day 240. Renal function has been normal, with no rejection for over 3.5 years. The second subject required treatment for possible humoral rejection at 6 weeks. Following return of normal renal function, immunosuppression was tapered slowly and was discontinued on day 422. Renal function has remained stable for the subsequent 2.5 years, with no evidence of rejection. In vitro assays of these two recipients showed donor specific unresponsiveness with no detectable anti-donor alloantibodies. The third subject developed early, irreversible humoral rejection, requiring retransplantation with conventional immunosuppression. The observations in subjects 2 and 3 led to revision of the regimen, in which pre-transplant anti-CD20 was added. The fourth subject was treated with the revised regimen and immunosuppression was discontinued on day 244. Renal function has remained stable, with no evidence of rejection for the subsequent five months. In vitro CML assays of this subject showed donor specific unresponsiveness. The fifth subject required treatment for the capillary leak syndrome with possible humoral rejection during the second week after transplant. The recipient is currently doing well with stable renal function under immunosuppression, which is planned to be withdrawn after 9 months.
CONCLUSIONS: Renal allograft tolerance has been induced successfully for the first time in recipients of one-haplotype HLA mismatched renal transplants. The conditioning regimen is evolving with the expectation that it can be more widely applied.
