Establishing donor specific tolerance in vascularized composite allotransplantation via local enrichment of endogenous regulatory T cells

Vascularized composite allotransplantation (VCA)—encompassing transplantation of hands/limbs and face is an emerging field with potential to restore the appearance and function of damaged tissue. Clinically, the process of rejection is suppressed via systemic immunosuppression, which is associated with a host of deleterious side effects. An alternative approach to prevent rejection is to harness the homeostatic mechanisms intrinsic to the immune system. To this end our group has recently developed controlled release microparticle (MP) systems capable of enriching Tregs at given location via synthetic cell constructs referred to as Expansion MP. Accordingly, we hypothesized that Treg enriching systems that release key cytokines, and immunosuppressive agents, can promote long term graft survival in preclinical VCA models. Following fabrication, Expansion MP was tested in an allogeneic rat hind limb transplant model and then in a swine gracilis myocutaneous flap allotransplant model. Following subcutaneous injection of microparticles, rodent hind limbs survived indefinitely (>200 days) and swine allografts survived until the end of the study period (4 weeks) with no signs of rejection. Secondary skin grafts and MLRs in both models demonstrate that ExpansionMP treatment appears to confer donor specific tolerance to recipients. Given these promising results, we believe this technology has the potential to dramatically impact the field of VCA and reconstructive transplantation.