Combined nonmyeloablative total lymphoid irradiation and low-dose total body irradiation enhances donor chimerism and leads to islet allograft acceptance

The nonmyeloablative conditioning regimen comprising total lymphoid irradiation (TLI) and antithymocyte globulin is used for allogeneic hematopoietic stem cell transplant patients. There is a need to safely intensify TLI+antithymocyte globulin to allow for the achievement of sustained mixed chimerism, particularly in cases where pre-existing autoimmunity poses a significant barrier to successful engraftment. We developed a nonmyeloablative immune preconditioning protocol using low-dose total body irradiation (TBI) to increase the level and durability of mixed donor chimerism. Non-obese diabetic mice were preconditioned with a modified protocol comprising TLI, low-dose TBI, and antithymocyte serum before bone marrow (BM) transplantation. The incorporation of low-dose TBI resulted in enhanced lymphodepletion and facilitated successful engraftment of allogeneic BM to create mixed donor chimerism. The establishment of mixed donor chimerism led to a long-term acceptance of transplanted pancreatic islets that were matched to the BM. More importantly, third-party islets from donors that were mismatched to both the recipient and BM donors were also accepted, highlighting the potency of tolerance induction using this preconditioning regimen. These results provide strong support for a rapid clinical evaluation of this modified conditioning regimen in the context of post-transplant tolerance induction.