Type 1 diabetes is characterized by beta-cell-specific autoimmune destruction, leading to life-long exogenous insulin-dependence. Islet transplantation can restore proper glycemic control, but graft longevity remains low due to immune-mediated rejection. The use of nanothin encapsulation materials consisting of poly (N-vinylpyrrolidone) (PVPON) and tannic acid (TA) , an antioxidant, can delay islet allograft rejection and decrease inflammatory immune responses. However, when (PVPON/TA) -encapsulated C57BL/6 islets were transplanted into streptozocin-treated diabetic NOD mice in the absence of systemic immunosuppression, only 50% of recipients maintained long-term allograft function. Therefore, modification of (PVPON/TA) coatings to include immune inhibitors are needed to prolong islet allograft survival. The adaptability of our (PVPON/TA) layers allow for its conjugation to CTLA-4-Ig, a fusion protein that can block CD28-mediated co-stimulation of T cells. We hypothesize that the addition of CTLA-4-Ig to (PVPON/TA) outer layers, denoted as (PVPON/TA/CTLA-4-Ig) , will extend islet allograft survival by inhibiting proinflammatory effector T cell responses. Transplantation of (PVPON/TA/CTLA-4-Ig) -encapsulated NOD.Rag islets significantly delayed islet allograft rejection in diabetic C57BL/6 mice compared to non- (p<0.0001) and control IgG-containing (PVPON/TA/IgG) -encapsulated islets (p<0.01) . Additionally, (PVPON/TA/CTLA-4-Ig) -encapsulation significantly increased FOXP3+ regulatory and CD73+ FR4+ anergic CD4+ T cell count when compared to both non- and (PVPON/TA/IgG) -encapsulation. Since CTLA-4-Ig can affect the tryptophan catabolism pathway, future studies will investigate the effect of (PVPON/TA/CTLA-4-Ig) -encapsulation on indolamine-2,3-dioxygenase expression in antigen-presenting cells. The success of (PVPON/TA/CTLA-4-Ig) coatings to delay allograft rejection warrant their use in future human translational studies.
J.Barra: None. K.S.Burnette: None. V.Kozlovskaya: None. E.Kharlampieva: None. H.M.Tse: None.
NIH/NIDDK Raward (DK099550) NIH/NIDDK Raward (DK127497) JDRF award (SRA-2016-270-S-B) JDRF award (2-SRA-2019-692-S-B) NIH/NIDDK R56 award (DK126456) NIH/NIDDK Raward (DK126456) NIH/NIGMS (T32GM109780) NIH/NIGMS (T32GM008111)