Improved conditioning for hematopoietic chimerism induces islet tolerance to cure diabetes

Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues. However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance. We sought agents that reduced conditioning intensity, while promoting durable mixed chimerism after HCT across complete major histocompatibility complex (MHC) mismatch in diabetic mice, permitting islet allotransplantation and diabetes reversal. We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and αCD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT. Combined with αCD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of GVHD. Thus, we have developed a conditioning regimen to promote allogeneic mixed hematopoietic chimerism and transplanted islet allotolerance that minimizes conditioning radiation and cures diabetes, a significant achievement.