Targeting Purinergic Receptors in Islet Transplantation

Abstract

Transplanted islets are exposed to a distinctively hostile immunological environment. Grafted islets typically encounter a combination of innate, allogeneic and anti-islet immune responses—the relative contributions of which are not fully understood. The relatively low success rate of islet transplantation compared with other organs suggests that current immunomodulatory protocols are inadequate to provide long-term islet graft protection. As the negative consequences of long-term immunosuppression can arguably outweigh the benefits of islet transplantation, there is intense focus on the development of strategies to induce immune tolerance toward grafts, thereby avoiding the requirement of chronic immunosuppression. In this issue of Diabetes , Vergani et al. (1) provide evidence that targeting purinergic receptor signaling is a viable strategy for islet allograft protection. Extracellular ATP modulates many aspects of the immune system. For example, ATP signaling is able to promote the differentiation of proinflammatory Th17 cells (2), which may play a role in islet rejection and recurrent autoimmunity. ATP signaling can also suppress the differentiation and function of regulatory T cells (Tregs) (3), which are immunosuppressive T cells that play a role in immune tolerance (4). Thus, ATP signaling acts to shift the immune response toward a more inflammatory, less tolerant state (Fig. 1). FIG. 1. Schematic summary of the proposed mechanism of action of ATP during islet allograft rejection. A : Extracellular ATP activates P2X receptors and promotes T-cell …