*Purpose: Transplantation of islets into hepatic portal vein is associated with significant islet mass loss immediate post-transplantation. Instant blood mediated inflammatory reaction (IBMIR), characterized by non-specific thrombotic and inflammatory reactions orchestrated by innate immune cells, is the main culprit of islet graft loss. CD47/SIRPα axis has been shown to play an important role in downregulating innate immune responses, including activation of neutrophils, platelets, macrophages, and dendritic cells. Thus, we assessed the efficacy of CD47/SIRPα innate immune checkpoint in enhancing islet graft engraftment by mitigating IBMIR.

*Methods: A synthetic gene encoding the extracellular domain of CD47 C-terminus to a modified form of streptavidin, (SA)-CD47, was generated and expressed in insect cells. SA-CD47 protein was purified and effectively displayed on the surface of biotinylated cells and islets by taking the advantage of high interaction between biotin and SA. The efficacy of SA-CD47 in enhancing engraftment and mitigating IBMIR was assessed in an in vitro loop assay as well as in vivo in an intraportal transplantation model.

*Results: Rat splenocytes engineered with SA-CD47 protein were refractory to phagocytosis by mouse macrophages. Biotinylation of islets followed by engineering with SA-CD47 protein did not impair islet viability and insulin secretion function. Importantly, SA-CD47-engineered islets showed significantly enhanced engraftment and survival as compared with SA-engineered controls in a minimal mass syngeneic intraportal transplantation model. SA-CD47-engineered islet recipients had significantly less intrahepatic infiltration of inflammatory cells and reduced levels of inflammatory mediators, including high-mobility group box-1, tissue factor, and IL-1β. Additionally, SA-CD47 protected islet morphology and blocked intra-islet infiltration of CD11b⁺ granulocytes.

*Conclusions: CD47 serves an effective innate immune checkpoint that mitigates IBMIR, leading to improved islet engraftment and survival with important clinical implication for auto and allogeneic islet transplantation.

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