Long-term outcome and alloantibody production in a non-myeloablative regimen for induction of renal allograft tolerance

Background. Multilineage chimerism and long-term acceptance of renal allogr afts has been produced in non-human primates conditioned with a nonmyeloabl ative regimen. Our study was undertaken to evaluate the immunological and p athological status of longterm survivors and to define the role of splenect omy and of the primarily vascularized kidney in the regimen. Method, Monkeys were treated with the basic regimen, including: total body irradiation, thymic irradiation, antithymocyte globulin, donor bone marrow transplantation, and a 4-week course of cyclosporine after which no further immunosuppression was given. They were divided into four groups according to the timing of kidney transplantation (KTx) and splenectomy as follows; g roup A (n=13): KTx and splenectomy on the day of donor bone marrow transpla ntation (day 0); group B (n=3): KTx on day 0 without splenectomy; group C ( n=7): splenectomy on day 0 but delayed KTx until 3 to 16 weeks post-donor b one marrow transplantation; group D (n=3): both splenectomy and KTx delayed until day 120 post-donor bone marrow transplantation. Results. In group A, 11 of 13 monkeys developed chimerism and 9 monkeys ach ieved long-term survival of 4 to 70 months without evidence of chronic vasc ular rejection. Alloantibodies were detected in only one long-term survivor . In contrast, all three monkeys in group B developed alloantibodies and re jected their allografts, In group C, long-term survival without alloantibod y production was observed in two of three monkeys that had developed chimer ism, In group D, all three recipients were sensitized and rejected the kidn ey allografts rapidly after transplantation. Conclusions. 1) Production of anti-donor antibody was prevented in most rec ipients that developed mixed chimerism in the regimens with splenectomy at the time of donor bone marrow transplantation. 2) If splenectomy is not inc luded in the initial conditioning regimen, induction of B cell tolerance is less likely and the result is late onset of alloantibody production and al lograft rejection. 3) Immediate transplantation of the kidney at the time o f recipient conditioning is not essential for induction of donor specific h yporesponsiveness by bone marrow transplantation.