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.

Public Health Relevance

Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of population worldwide. Insulin as a standard treatment has major long-term complications; therefore, the development of novel approaches to prevent and treat T1D is a significant therapeutic goal. The primary objective of this proposal is to develop an immunomodulatory protocol that prevents the rejection of pancreatic allogeneic islets for the treatment of T1D. If effective, this approach will have immediate and important implications for the use of allogeneic islets for the treatment of T1D in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI121281-01A1
Application #
9661572
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2018-11-05
Project End
2023-10-31
Budget Start
2018-11-05
Budget End
2019-10-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Louisville
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292