164-OR: Brown Adipose Tissue as a Novel Site for Islet Transplantation

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells. While islet transplantation is a promising alternative to insulin therapy for T1D treatment, finding ideal transplant sites that are readily accessible, exhibit glucose regulation, are immune-privileged, and promote vascularization for islet survival has remained a challenge. A novel site which exhibits these traits is the brown adipose tissue (BAT). BAT functions as a thermogenic adipose tissue that maintains body temperature and regulates metabolism. We hypothesize that murine islets transplanted into BAT will display normal islet graft and BAT function while providing immunological protection. Syngeneic transplant of 250 NOD.scid islets into the BAT of streptozotocin-treated diabetic NOD.scid mice restored euglycemia for over ten weeks, which was comparable to kidney capsule transplant controls. BAT histology and mRNA analysis assessed ten weeks after transplantation showed engrafted islets maintain expression of hallmark hormones, like insulin and glucagon, and critical transcription factors. Evaluation of BAT function after transplantation revealed no impairments in glucose and insulin tolerance, cold tolerance, or whole-body energy expenditure. Flow cytometry analysis displayed an enrichment of immunomodulatory T regulatory cells and anti-inflammatory M2 macrophages in BAT compared to kidney, possibly allowing greater immunoprotection for engrafted islets. Strikingly, adoptive transfer and allogeneic transplant studies revealed that islets transplanted into BAT showed significant delays in autoimmune and allograft rejection compared to islets transplanted under the kidney capsule. Overall, our data suggest BAT as a novel and efficacious site for islet transplantation to potentially combat T1D.