Strategies to attenuate the indirect alloimmune response in encapsulated pancreatic islet transplantation

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Project Summary Type 1 diabetes (T1D) is an autoimmune condition that destroys the insulin-producing beta cells within the pancreatic islets of Langerhans. Although the treatment for T1D is aided with new technology like continuous glucose monitoring and automated insulin pumps, exogenous insulin administration is the core management strategy and T1D remains a life-changing and lifelong diagnosis. T1D can be cured by beta cell replacement through pancreatic islet transplantation, however the need for chronic systemic immunosuppression greatly limits the applicability of this procedure. Encapsulation of islets within selectively permeable hydrogels prior to transplantation may eliminate the need for chronic immunosuppression by blocking direct recipient cell and antibody contact with allogeneic islets. The Tomei lab has developed a unique encapsulation method, “conformal coating,” that addresses several considerations of traditional encapsulation methods. Altogether, islet encapsulation has been shown in animal models of T1D to be capable of restoring blood glucose regulation, however recipient innate and adaptive immune cells including macrophages and T cells still initiate a local inflammatory and pericapsular response and limit the long-term efficacy of encapsulated islet transplantation. Given the selective permeability of the hydrogel layer, soluble alloantigens shed by the transplanted islets are likely triggering an indirect allorecognition pathway, where recipient professional antigen-presenting cells scavenge and present alloantigens shed by transplanted islets to alloreactive T cells while simultaneously providing co-stimulatory signal activation. The overall goal of my project is to capitalize on this mechanism by blocking the co-stimulatory pathways required for T cell activation. I hypothesize that combining encapsulated islet transplantation with (1) localized and targeted nanoparticle delivery of biologic co-stimulatory blockers (cytotoxic T lymphocyte antigen 4 immunoglobulin) or (2) co-transplantation with immunomodulatory non- professional antigen presenting cells (that present antigen but do not provide adequate co-stimulation) will induce deletion/anergy of alloreactive T cells and promote tolerance to transplanted islets, thereby improving and prolonging their efficacy in restoring physiologic metabolic control.