Type I diabetes is a chronic autoimmune that affects 3 million children and adults in the US with healthcare
costs exceeding $14.9 billion annually. Currently, there is no cure for type 1 diabetes, representing a critical
unmet medical need. Transplantation of allogeneic islets is a reliable method of achieving durable glucose
homeostasis and preventing the devastating complications of type 1 diabetes. However, there are four major
barriers to allogeneic islet transplantation; i) ineffective engraftment, ii) rejection, iii) adverse effects of
immunosuppression used to control rejection, and iv) shortage of cadaveric donor islets. Therefore, there is a
significant need for strategies that overcome these limitations of islet transplantation for a broader clinical practice.
This R01 application aims to develop an innovative and highly translational immunomodulatory protocol to
overcome the limitations of islet transplantation for sustained long-term graft survival in the absence of
chronic use of immunosuppression.
Infusion of islets into the liver via portal vein, the only route of transplantation in clinical use, instantly
exposes the graft to blood and initiates an immediate blood-mediated inflammatory reaction (IBMIR). IBMIR is
mediated by thrombotic and inflammatory reactions and is responsible for the destruction of 50-80% islets
immediate post-transplantation. The remaining islets are then subject to rejection by the slower, but potent
adaptive immune responses. Significant early islet loss requires transplantation from 2-3 donors per
recipients, which further contribute to the shortage of cadaveric donors. The goal of this proposal is to
develop powerful, yet focused therapies to simultaneously target the immediate inflammatory
reactions and adaptive immune response to prevent early and late graft loss. This will be accomplished
by generating novel recombinant proteins with robust inhibitory functions on prothrombotic, proinflammatory,
and adaptive immune reactions. These proteins will be engineered on pancreatic islets before transplantation
for localized modulation of thrombotic and inflammatory responses to enhance engraftment and achieve
indefinite graft survival without the chronic use of debilitating immunosuppression that is currently standard.
This concept will be tested in three different allogeneic islet transplantation settings for efficacy and
mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice, spontaneously diabetic C57BL/6-to-NOD mice,
and human islets into humanized mice. These models will generate critical data relevant to the human setting.
Furthermore, proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomes
will expedite further refinement of this immunomodulatory concept and its eventual translation to nonhuman
primates as a prelude to clinical trials for the treatment of type 1 diabetes.