Chimeric Thrombomodulin and CD47 proteins synergistically improve the engraftment of islets by mitigating IBMIR
No Thumbnail Available
Authors
Meeting name
Sponsors
Date
Journal Title
Format
Thesis
Subject
Abstract
The main aim of this dissertation was to display novel immunological ligands, Thrombomodulin (TM) and CD47, on the surface of islets to promote islet engraftment by controlling thrombotic/inflammatory reactions associated with an immediate blood-mediated inflammatory response (IBMIR). In chapter 3, syngeneic pancreatic islets are engineered with a novel form of TM (SA-TM) to maintain euglycemia by preventing the immediate loss of islet transplant grafts. In chapter 4, the pancreatic islet was engineered with SA-TM and CD47 combination to prevent IBMIR from contributing to islet engraftment in a model of syngeneic marginal mass islet transplantation. Islet-blood interaction initiates IBMIR consisting of activation of the coagulation and complement systems and recruitment of myeloid cells, resulting in most initial graft loss. TM is an important regulator of coagulation and a cofactor of Activated Protein C (APC). TM and APC modulate the homeostasis of thrombosis, diminish the release of inflammatory mediators, and inhibit the immune cell infiltration into islet grafts. Moreover, CD47 binds to signal regulatory protein alpha (SIRP[alpha]), delivering a "do not eat me signal" to suppress phagocytosis and inhibition of myeloid cell activation. Hence, we hypothesized that SA-TM and SA-CD47 combination on islets maintain islet engraftments in a syngeneic marginal mass model of intraportal transplantation by mitigating thrombotic/inflammatory reactions. 200 IEQ islet engineered with SA-TM and transplanted into syngeneic STZ-induced diabetic mice. Recipients with SA-TM-engineered islets demonstrated better outcomes compared to recipients whose-islets engineered with SA served as controls (83 vs 28 percent). There was a significant reduction in the graft infiltration immune cells and the gene expression of inflammatory genes, such as High mobility group box 1 (HMGB-1), Tissue Factor (TF), and Interleukin 6 (IL-6), associated with IBMIR. To show the efficiency of combinational, we herein engineered 150 IEQ islets with SA-TM or SA-TM/SA-CD47. Importantly, SA-TM/SA-CD47-engineered islets showed improved engraftment, and long-term function in a syngeneic minimal mass model of intraportal islet transplantation compared to SA-TM engineered or unmodified islet served control (62.5 percent, vs 50 percent and 29 percent respectively). Enhanced survival revealed the decreased recruitment of myeloid cells and levels of numerous genes related to IBMIR and proinflammatory signals and hypoxia. Overall, SA-TM and SA-CD47 displayed on the islets serve as an effective platform to prevent IBMIR with important clinical implications for islet transplantation to treat type 1 diabetes and chronic pancreatitis.
Table of Contents
PubMed ID
Degree
Ph. D.