Islet transplantation can restore glucose homeostasis in patients with type 1 diabetes (T1D), however, limited islet availability, toxicity of immunosuppressants, and poor graft survival impede clinical application. We hypothesize that islet encapsulation with coatings consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), will provide immunoprotection and maintain β-cell function after transplantation. (PVPON/TA)-encapsulated syngeneic islets (n=13) significantly delayed graft failure without immunosuppression after transplantation under the kidney capsule into diabetic non-obese diabetic (NOD) mice by more than 30 days compared to non-encapsulated grafts (n= 13; p=0.0021). Histology of islet engrafted kidneys demonstrated increased insulin, glucagon, and somatostatin positivity within encapsulated grafts compared to non-encapsulated grafts and was corroborated with enhanced glucose responsiveness following an intraperitoneal glucose tolerance test (n=9, p=0.0032). To define the immunoprotective properties of (PVPON/TA) coatings, flow cytometric analysis of islet grafts at day 7 post-transplantation displayed fewer MHC-II expressing cells compared to non-encapsulated controls. Gene expression of islet grafts at 5 days post-transplant displayed a significant increase in Ins2 (p<0.05), Arg1 (p<0.0001), and a decrease in Ccl5 (p=0.0006), Cxcl10 (p=0.043), and Grzmb (p=0.032) mRNA accumulation in encapsulated islet grafts in contrast to controls, suggesting that (PVPON/TA)-encapsulation reduces proinflammatory immune responses and elicits a shift toward an anti-inflammatory phenotype. To address limited islet availability, encapsulation of neonatal porcine islets restored euglycemia in diabetic NOD.scidmice for more than 200 days after xenotransplantation. Our results support the hypothesis that (PVPON/TA) coatings are immunomodulatory and may prolong islet graft function following transplantation.
J. Barra: None. V. Kozlovskaya: None. E. Kharlampieva: None. G. Korbutt: None. H.M. Tse: None.
American Diabetes Association (7-12-CD-11 to H.M.T.); JDRF (1-SRA-2015-42-A-N)