Immune-checkpoint engineered islets as beta cell replacement therapy for type I diabetes

About This Grant

Type 1 diabetes (T1D) is viewed as a T cell-mediated autoimmune disease resulting in insulin deficiency due to the lack of functional pancreatic islet beta (β) cell mass. Despite significant advances in insulin replacement therapies, there continues to be an urgent need for treatments that can recapitulate physiologic insulin release. The most promising approach is allogeneic β cell replacement but immune reaction is a key challenge. Our group has developed a novel approach in which β cells are bioengineered to contain high levels of multiple types of immune checkpoint ligands. We found that engineered β cells can induce long term durable tolerance in allogeneic transplantation without the need for immune suppression. We have further identified that the most effective immune checkpoint combination for engineered β cells. The goal of this proposal is to optimize key steps of our engineering platform to enhance therapeutic efficacy, while defining immunological events that reestablish self-tolerance. Our application has 3 Specific Aims. The first Aim will to optimizing the tolerogenic formulation for allogeneic β cell transplantation. This involves examining PD-L1/HVEM ratio and ligand density in inducing transplant tolerance. The second Aim will study an approach where the decellularized pancreas matrix is engineered with immune checkpoint molecules. The success of this aim will improve translatability of this technology. Aim 3 will determine the mechanisms of tolerance induction and maintenance. Our application incorporates advances in chemistry, chemical biology, nanotechnology, and immunology to improve T1D treatment. Our findings can be rapidly translated and hold high potential for clinical impact.