Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation

Abstract

Significance Vascularized composite allotransplantation (VCA) is an emerging field that is particularly beneficial for select amputees and patients with devastating soft tissue loss that is not amenable to conventional reconstructive surgeries. As with solid organ transplantation, VCA recipients are subjected to a lifelong regimen of antirejection drugs with a well-established sequela. Herein, we report a synthetic, controlled-release microparticle system (referred to as TRI-MP) that aims to locally enrich naturally occurring, suppressive lymphocytes to prevent allograft rejection and promote tolerance. While this study exclusively focuses on VCA, this technology has implications for other conditions characterized by aberrant inflammation. For individuals who sustain devastating composite tissue loss, vascularized composite allotransplantation (VCA; e.g., hand and face transplantation) has the potential to restore appearance and function of the damaged tissues. As with solid organ transplantation, however, rejection must be controlled by multidrug systemic immunosuppression with substantial side effects. As an alternative therapeutic approach inspired by natural mechanisms the body uses to control inflammation, we developed a system to enrich regulatory T cells (Tregs) in an allograft. Microparticles were engineered to sustainably release TGF-β1, IL-2, and rapamycin, to induce Treg differentiation from naïve T cells. In a rat hindlimb VCA model, local administration of this Treg-inducing system, referred to as TRI-MP, prolonged allograft survival indefinitely without long-term systemic immunosuppression. TRI-MP treatment reduced expression of inflammatory mediators and enhanced expression of Treg-associated cytokines in allograft tissue. TRI-MP also enriched Treg and reduced inflammatory Th1 populations in allograft draining lymph nodes. This local immunotherapy imparted systemic donor-specific tolerance in otherwise immunocompetent rats, as evidenced by acceptance of secondary skin grafts from the hindlimb donor strain and rejection of skin grafts from a third-party donor strain. Ultimately, this therapeutic approach may reduce, or even eliminate, the need for systemic immunosuppression in VCA or solid organ transplantation.