In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation

摘要

Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (Tsubreg/sub) to suppress inflammation. Specifically, a microparticle-based system engineered to release the Tsubreg/sub-recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These “Recruitment-MP” prolonged hindlimb allograft survival indefinitely (200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched Tsubreg/sub populations in allograft skin and draining lymph nodes and enhanced Tsubreg/sub function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human Tsubreg/sub in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive Tsubreg/sub.