Donor macrophage depletion permits posttransplant tolerance induction in a murine islet transplant model

Current strategies for experimental tolerance induction for allogeneic transplantation typically require recipient preparation days to weeks prior to transplantation, making them not applicable to deceased-donor transplantation. Developing tolerance strategies feasible for deceased-donor transplantation would greatly increase the pool of eligible patients for tolerance induction. Here, we aimed to induce tolerance with posttransplant-only interventions in a murine pancreatic islet transplant model. We demonstrated that transplant tolerance induction by recipient infusions of ethylcarbodiimide-treated donor splenocytes could be reliably delayed to the posttransplant timeframe, provided that donor islets were depleted of intraislet macrophages prior to transplantation. Mechanistically, islet production of C-C chemokine ligand (CCL)3, CCL4, and CCL5 was significantly reduced by intraislet macrophage depletion. On postoperative day +1, islet allografts depleted of donor intraislet macrophages exhibited significantly reduced infiltration of recipient innate immune cells, including monocytes, macrophages, and neutrophils. Interestingly, perioperative inhibition of C-C chemokine receptor 5, the receptor for CCL3, CCL4, and CCL5, also reduced postoperative day +1 innate immune cell infiltration, and similarly permitted tolerance induction by posttransplant donor ethylcarbodiimide-treated splenocyte infusions. This study, thus, demonstrates the efficacy of a strategy that would allow transplant tolerance induction by posttransplant-only interventions, thereby expanding the applicability of tolerance induction regimens to additional clinically relevant settings.