Engineering pancreatic islets with a novel form of thrombomodulin protein to overcome early graft loss triggered by instant blood-mediated inflammatory reaction.

Instant blood-mediated inflammatory reaction (IBMIR) is initiated by innate immune responses that cause substantial islet loss following intraportal transplantation. Thrombomodulin (TM) is a multifaceted innate immune modulator. We report the generation of a chimeric form of this molecule with streptavidin (SA-TM) for transient display on the surface of islets modified with biotin to mitigate IBMIR. SA-TM protein expressed in insect cells showed the expected structural and functional features. SA-TM converted protein C into activated protein C, blocked phagocytosis of xenogeneic cells by mouse macrophages, and inhibited neutrophil activation. SA-TM was effectively displayed on the surface of biotinylated islets without a negative impact on their viability or function. Islets engineered with SA-TM showed improved engraftment and established euglycemia in 83% of diabetic recipients as compared to 29% recipients transplanted with SA-engineered islets as control in a syngeneic minimal mass intraportal transplantation model. Enhanced engraftment and function of SA-TM-engineered islets were associated with inhibition of intragraft proinflammatory innate cellular and soluble mediators of IBMIR, including macrophages, neutrophils, HMGB1, TF, MCP-1, IL-1β, IL-6, TNF-α, IFN-γ. Transient display of SA-TM protein on islet surface to modulate innate immune responses causing islet graft destruction has clinical potential for autologous and allogeneic islet transplantation.