165-OR: Antioxidant-Based Encapsulation Strategies to Enhance Islet Allotransplantation

Abstract

The destruction of insulin-producing cells is a hallmark of type 1 diabetes (T1D) and results in a loss of glycemic control. Islet transplantation can restore glucose homeostasis and prevent hypoglycemic events; however, long-term graft survival is low. Oxidative stress mediates islet transplant rejection. Therefore, suppressing oxidative stress with nanothin encapsulation materials comprised of alternating layers of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), a scaffold polymer, may allow for improved graft survival. We hypothesize that (PVPON/TA)-encapsulation of islets will prolong graft function and delay allotransplantation rejection in the absence of systemic immunosuppression. We recently published that allogeneic transplantation of encapsulated C57BL/6 islets into NOD mice significantly delayed graft failure, decreased free radical-adduct formation, and reduced infiltrating immune cell effector responses. These data suggest local immunosuppression with (PVPON/TA)-encapsulation may be a promising technique to prolong islet graft function in islet allotransplants. To enhance immunosuppression, we conjugated CTLA-4-Ig to the outer surface of (PVPON/TA) layers. (PVPON/TA/CTLA-4)-encapsulated islets display significantly delayed allograft rejection compared to (PVPON/TA) controls. Flow cytometry analysis demonstrated reduced CD80/CD86 costimulatory receptor and MHC-II expression on innate immune populations, enhanced FOXP3+ regulatory T cells, and enhanced PD1+ CD8 T cells within (PVPON/TA/CTLA-4)-encapsulated grafts. To monitor graft integrity in vivo, we conjugated (PVPON/TA) layers with the fluorophore Cy5.5. Transplantation of (PVPON/TA/Cy5.5)-encapsulated islets restored glucose tolerance and was detected in vivo for up to eight weeks post-transplant. The ability to modify our (PVPON/TA) coatings opens the door for endless possibilities to improve clinical islet transplantation. Disclosure J. Barra: None. V. Kozlovskaya: None. E. Kharlampieva: None. H. M. Tse: None. Funding National Science Foundation (1608728); National Institute of Diabetes and Digestive and Kidney Diseases (DK-099550); JDRF (SRA-2016-270-S-B, 2-SRA-2019-692-S-B)