Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic b-cell destruction. Islet-infiltrating leukocytes will generate reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules involved in b-cell lysis. Islet transplantation is a promising treatment for T1D, but numerous hurdles including immune-mediated rejection, adverse effects of immunosuppression on islet function, ideal sites for transplantation, and declining allograft survival impede human translatability. Islet encapsulation may provide immunoprotection to preserve islet function and prevent immune responses against the islet graft following transplantation. The goal of this project is to assess the efficacy of a pre-vascularized subcutaneous device-less (DL) site for transplantation and to enhance a novel cytoprotective coating for islet encapsulation consisting of a layer-by-layer hydrogen-bonded assembly of tannic acid (TA), an immunomodulatory antioxidant, poly(N-vinylpyrrolidone) (PVPON), a cytocompatible natural and synthetic polymer, and CTLA-4-Ig to inhibit T cell activation in mouse models and humanized mouse models of islet allotransplantation. Transplantation of (PVPON/TA/CTLA-4-Ig)-encapsulated islets in the DL site are functional, does not elicit a foreign body reaction unlike the microencapsulated devices currently being evaluated in clinical trials, can decrease proinflammatory immune responses, and delay allograft rejection in the absence of global immunosuppression. Our overarching hypothesis is that (PVPON/TA/CTLA-4-Ig) encapsulation of islets can elicit localized immunosuppression and preserve islet function following transplantation into a pre-vascularized device-less site without stimulated deleterious fibrosis. To address this hypothesis, the following independent and interrelated aims will be defined in mouse and human samples. (1) Determine if (PVPON/TA/CTLA-4-Ig) encapsulation can suppress proinflammatory innate and adaptive immune responses after transplantation. (2) Determine if (PVPON/TA/CTLA-4-Ig) encapsulation stabilizes b-cell function and decreases inflammation. The insights gained from our studies will identify additional pathways that can be exploited to conjugate novel inhibitors of proinflammatory immune responses to our adaptable (PVPON/TA/CTLA-4-Ig) coatings to further delay islet allograft rejection for future human translational studies.

Project Narrative Islet transplantation is a cure for Type 1 diabetes, but transplanted islets are susceptible to immune-mediated destruction. Encapsulation of islets with a protective biomaterial that retains insulin secretion, but also prevents recognition by the immune system is highly desired. We will determine if islet encapsulation with a novel antioxidant and immune system modulator, tannic acid and CTLA-4-Ig, respectively, can mediate immune suppression and prolong islet function after transplantation in a subcutaneous site.