Graft-versus-host disease enhanced by extracellular adenosine triphosphate activating P2X7R

Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction like it is found in acute graft-versus-host disease (GvHD), allograft rejection and systemic inflammatory response syndrome. Based on its minor concentration in the extracellular space under physiological conditions1, and the expression of its receptor P2X7R on different immune cells, adenosine triphosphate (ATP) could function as a danger signal when released from dying cells. We observed increased ATP levels in the peritoneal fluid following total body irradiation, and during the development of GvHD in the mouse and in humans. Stimulation of host type antigen-presenting cells (APC) by ATP led to increased expression of CD80/CD86 and actuated a cascade of proinflammatory events, including STAT1 phosphorylation, IFN-γ production and donor type T cell expansion, while regulatory T cell frequencies were simultaneously reduced. P2X7R expression increased when GvHD evolved, rendering APC more responsive to the detrimental effects of ATP, thereby providing positive feed-back signals. ATP neutralization, P2X7R blockade or genetic deficiency during GvHD development significantly improved survival without global immune paralysis. These data have major implications for transplantation medicine since pharmacological interference with danger signals that act via P2X7R could lead to the development of tolerance, without the need for intensive immunosuppressio