Cardiac transplantation is established therapy for the treatment of end-stage heart failure. However, chronic rejection in the form of accelerated arteriosclerosis remains the primary cause of late death after heart transplantation. Despite the development of several new drugs to combat rejection, the incidence of this form of chronic rejection has not changed. We have hypothesized that endothelial cells, which line coronary arteries, are capable of directly activating CD8+ T cells, which may play an important role in the development of graft vascular disease. We have established both in vitro and in vivo mouse models to study this process. The broad objective of this grant proposal is to define the differences in the ability of murine endothelium to activate CD4+ and CD8+ T cells in vitro and then to use analogous in vivo models to define the allorecognition pathways and effector mechanisms responsible for graft vascular disease. To achieve this goal, we will: 1. Test the hypothesis that endothelium activates both unprimed and primed CD8t T cells preferentially due to a less stringent requirement for costimulation. 2. Test the hypothesis that endothelium is a suitable target for CD8+ T cell cytotoxicity predominantly via the Fas/FasL pathway. 3. Test the hypothesis that graft vascular disease is a CDK about-dependent process. In summary, this proposal will determine whether endothelium has the capacity to stimulate CD8F T cells and the ability to act as targets for CD8+ cytotoxic T cells, which is sufficient to induce graft vasculopathy in a mouse model. Insights from this study will undoubtedly provide information that will lead to rational strategies to help prevent this lethal complication of human heart transplantation.
