| Allograft blood vessels are important targets of clinical allograft rejection. Peri-operative allograft injury to graft vasculature, especially the endothelial cell (EC) lining, appears to increase the risk of subsequent acute and chronic vascular rejection. We have hypothesized that allograft EC injured by peri-operative ischemia-reperfusion (I/R) release mediators, termed "alarmins," that alter and intensify the host anti-graft adaptive immune response. Here we demonstrate that injury to endothelial cells can result in the release of interleukin (IL)-1 through several mechanisms, including (1) passive release of bioactive IL-1alpha, (2) active expression of cell surface-associated IL-1alpha, and (3) stimulation of monocyte IL-1beta secretion through release of HMGB1. IL-1 modulates adaptive immune responses by acting on T cells, including memory T cells, to enhance production of pathogenic cytokines such as IFN-gamma and IL-17. Using a human-mouse chimeric model of human artery allograft rejection, we demonstrate that IL-1 within the artery graft promotes IL-17 expression by infiltrating alloreactive T cells, which drives a pro-inflammatory cascade during T cell-mediated rejection. Further, we show that IL-1 blockade reduces the extent of human T cell infiltration into the artery intima, thereby inhibiting intimal expansion and pathologic remodeling. These results suggest that IL-1 is a key link between injury and adaptive alloimmunity that may preferentially enhance IL-17-mediated inflammation. The protective effects of IL-1 blockade in our model suggest that therapeutic targeting of IL-1 in the perioperative period represents a promising strategy to dampen the pathogenic effects of cadaver graft injury on host adaptive alloimmunity and thereby ameliorate the severity of allograft rejection. If correct, this conclusion carries significant clinical implications both for transplantation and in other, more common settings in which tissue injury may alter pathologic adaptive immune responses, e.g. stroke. |
