Mixed chimerism following non-myeloablative stem cell transplantation (Nst) To induce transplantation tolerance to bone marrow and organ allografts

Abstract

Abstract Durable engraftment of donor hematopoietic stem cells results in long lasting transplantation tolerance to donor alloantigens; mixed chimerism (MC) induced during fetal life or neonatally, results in life-long transplantation tolerance to donor alloantigens, using no pre- or post transplant immunosuppression. We showed previously that induction of MC in immunocompetent recipients conditioned by total lymphoid irradiation (TLI) results in permanent, specific transplantation tolerance to donor alloantigens with permanent engraftment of heart, pancreatic islets and full thickness skins. MC can be clinically induced by non-myeloablative stem cell transplantation. Host hematopoietic cells in MC may down-regulate donor anti-host alloreactivity, minimizing graft vs host disease, immunocompetent donor T lymphocytes may facilitate engraftment of donor hematopoietic cells, down-regulating residual host immunocompetent lymphocytes. Data from C57BL/6→ BALB/c chimeras show that MC with bilateral transplantation tolerance is inducible by deletion of host anti-donor alloreactive cells through activation-induced apoptosis, after stimulation of activated lymphocytes by donor alloantigens. Here we have induced host vs graft and graft vs host transplantation tolerance using NST, i.e. 1–6 fractions of TLI 200 cGy each, followed by deletion of BALB/c and C57BL/6 anti-alloreactive T lymphocytes by cytoxan 120–200 mg/kg as preparation for a 2 nd bone marrow transplantation 1 day later. Recipients accept donor skin allografts permanently (>200 days). Induction of permanent transplantation tolerance to donor alloantigens to gradually replace host with donor hematopoietic cells in hematologic, genetic and autoimmune diseases will be presented.