Clinical islet transplantation (CIT) is a potential therapy for type 1 diabetes. Allorejection mediated by the host CD4 T cells is a major hurdle for successful CIT, despite potent systemic immunosuppression (SI). To address these issues, we engineered PLGA microparticles (PLGA-MPs) that allow the localized delivery of TGF-β1 for regulatory T cells (TRegs) induction at the transplant site. TGF-β1 is an immunoregulatory agent that promotes the TRegs differentiation from naïve CD4 cells by inducing FoxP3 expression while suppressing inflammatory Th1 and Th2 responses. To date, we have (i) fabricated TGF-β1 loaded PLGA particles by double emulsion (PVA(aq)- CH2Cl2- PVA(aq)) with characterization in size (45±26 μm), TGF-β1 encapsulation efficiency (49.1±0.1%), and release kinetics (durable biphasic release for 14 days); (ii) proved effective TRegs conversion in OVA-OTII antigen-specific murine model (Fig.1); and (iii) shown efficacy for in vivo Treg conversion by MPs in rodent islet allografts, where accepted grafts showed improved insulin production and elevated TRegs. Future studies exploring the competency of PLGA-MPs to provide durable allograft protection in rodent models is on-going. Based on these promising preliminary results, TGF-β1 PLGA-MPs could provide a translational therapeutic strategy to minimize islet graft rejection and the dependency on SI.
Y. Li: None. A. Frei: Employee; Self; Medline Industries, Inc.. S.D. Barash: None. C.L. Stabler: None.
