Characterizing and overcoming innate immunity in beta-cell replacement therapy

In clinical islet transplantation, the engrafted islet cell mass is a critical factor for maintaining graft function and transplant outcome. This review dissects components that contribute to an acute innate immune response, including ischemia-reperfusion injury, damage-associated molecular patterns, islet-derived cytokines (isletokines), and an instant blood-mediated inflammatory reaction. The cyclical amplification of immune cell response and islet inflammation can occur at each stage of the transplant process. As such, strategies to improve islet transplantation include minimizing islet and immune cell cytokine production prior to procurement; suppressing the pretransplant islet immune inflammatory response; inhibiting the instant blood-mediated inflammatory reaction in the liver; preventing an innate immune response by encapsulation and islet surface modification; targeting cytokine/chemokine secretion and innate immune cell infiltration; considering the optimal site for islet engraftment; blocking cytokine signaling in islets; and implementing anti-inflammatory strategies to improve islet transplantation. A large body of evidence indicates that targeting immune components at multiple steps throughout the transplant procedure can improve overall islet transplant outcomes.