Abstract
The goal of conditioning for nonmyeloablative allogeneic stem cell transplantation, or NST, is to permit the stable engraftment of donor cells with a minimum of toxicity to the patient. We have previously developed a minimal conditioning regimen, consisting of low dose total body irradiation (TBI; 100–200 cGy) and post-transplantation cyclophosphamide (Cy), that permits the induction of stable mixed hematopoietic chimerism following the transplantation of modest doses of MHC-identical allogeneic stem cells in mice. The goal of the current study was to determine whether intravenous (IV) busulfan (Busulfex; ESP Pharma, Edison, NJ), an agent with myelotoxic but minimal immunosuppressive activity, could be used in place of TBI in this regimen and still promote allograft tolerance. TBI was more immunosuppressive than Busulfex, because engraftment of allogeneic stem cells could be achieved in mice conditioned with 700 cGy TBI alone but not in mice conditioned with an equivalently myelotoxic dose of 60 mg/kg Busulfex IV. However, when post-transplantation Cy was added, stable mixed hematopoietic chimerism was achieved in mice conditioned with doses as low as 100 cGy TBI or 20 mg/kg Busulfex. Busulfex and post-transplantation Cy were both required for the induction of allograft tolerance, because graft rejection occurred in transplanted mice treated with either agent alone. The capacity of Busulfex to promote allograft tolerance in this model could not be explained by effects of the drug on the host immune system, because the graft rejection response was not restored in Busulfex-conditioned mice reconstituted with mature host lymphocytes at the time of transplantation. These results demonstrate that Busulfex effectively substitutes for TBI in promoting allograft tolerance, and suggests that the creation of marrow “space” promotes alloengraftment in conditions of suboptimal host immunosuppression.
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