Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning

Mixed hematopoietic chimerism can promote immune tolerance of donor-matched transplanted tissues, like pancreatic islets. However, adoption of this strategy is limited by the toxicity of standard treatments that enable donor hematopoietic cell engraftment. Here, we address these concerns with a non-myeloablative conditioning regimen that enables hematopoietic chimerism and allograft tolerance across fully mismatched major histocompatibility complex (MHC) barriers. Treatment with an αCD117 antibody, targeting c-Kit, administered with T cell-depleting antibodies and low-dose radiation permits durable multi-lineage chimerism in immunocompetent mice following hematopoietic cell transplant. In diabetic mice, co-transplantation of donor-matched islets and hematopoietic cells durably corrects diabetes without chronic immunosuppression and no appreciable evidence of graft-versus-host disease (GVHD). Donor-derived thymic antigen-presenting cells and host-derived peripheral regulatory T cells are likely mediators of allotolerance. These findings provide the foundation for safer bone marrow conditioning and cell transplantation regimens to establish hematopoietic chimerism and islet allograft tolerance. [Display omitted] •Stable mixed hematopoietic chimerism achieved without myeloablative conditioning•Chimerism confers allotolerance to MHC-mismatched islets without immunosuppression•Simultaneous hematopoietic cell and islet transplantation durably corrects diabetes•Central and peripheral tolerance mechanisms likely mediate islet allotolerance Pancreatic islet transplantation in diabetes is limited by requirements for systemic immunosuppression to prevent rejection. Chang et al. report a non-toxic bone marrow conditioning regimen targeting c-Kit that permits stable mixed hematopoietic chimerism across major histocompatibility complex barriers, promoting allotolerance to transplanted islets without systemic immunosuppression and durable diabetes correction.