Engineering islet surface with a novel form of thrombomodulin protein to mitigate instant blood-mediated inflammatory reaction following intraportal transplantation

Abstract Intraportal infusion of islets initiates an innate immune response termed instant blood-mediated inflammatory reaction (IBMIR) that is responsible for significant islet mass peritransplant. We herein used thrombomodulin (TM) as a multifaceted regulator to mitigate IBMIR prevent the destruction in minimal syngeneic intraportal transplantation model. A novel form TM molecule chimeric with streptavidin (SA-TM) was produced insect cells and characterized structure attachment biotinylated cell surface taking advantage high affinity interaction biotin (SA). Islets were engineered SA-TM assessed ability vitro blood loop assay survival following (200 IEQ/mouse) STZ diabetic mice (n=7). SA-engineered served control (n=6). Animals monitored engraftment subjected various mechanistic studies. prevented phagocytosis xenogeneic by macrophages inhibited neutrophil NETs formation. Engineering did not impact viability function damage assay. SA-TM-engineered showed enhanced compared (83% vs 29%) transplantation. Enhanced associated decreased frequency intragraft myeloid expression mediators, such HMGB-1, tissue factor, IL-1β. protein provides facile clinically applicable approach modulate responses prevention potential applications allo/auto Funded parts NIH U01AI132817 R01AI121281 grants.