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

Abstract

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 (T_reg) to suppress inflammation. Specifically, a microparticle-based system engineered to release the T_reg-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 T_reg populations in allograft skin and draining lymph nodes and enhanced T_reg function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human T_reg in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive T_reg.