The role of ischaemia reperfusion injury and mitochondrial dysfunction in the development of chronic allograft vasculopathy

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Transplantation is the life-saving treatment for end-stage organ failure, including heart, kidney and liver. Transplantation outcomes have improved significantly in recent decades, but chronic rejection remains one of the major challenges facing solid organ transplantation today. Recognition of the transplanted organ by the immune system as foreign is central to this process. There is, however, increasing evidence that the interruption and subsequent restoration of oxygenated blood flow to the organ at the time of transplantation, known as ischaemia reperfusion injury (IRI), can not only result in initial organ damage but can also exacerbate chronic rejection. The exact mechanism by which IRI exacerbates chronic rejection is still to be elucidated and there are no established treatments to ameliorate IRI.Mitochondria are intracellular organelles that are critical for energy production within cells and play a key role in mediating the damaging effects of IRI. Recently, specific mitochondrial-targeted therapies have been developed that have been shown to attenuate IRI. These have already been shown to be safe and effective in extensive animal models and human clinical trials. Their application to transplantation is therefore, very appealing. This project will use well-established mouse heart transplant models of chronic rejection to examine the mechanisms by which mitochondrial dysfunction and IRI interact with the immune system to exacerbate chronic rejection. Furthermore, the efficacy of mitochondria-targeted therapies in ameliorating chronic rejection after transplantation will be established. We aim to show that IRI has a significant detrimental impact on long term graft outcomes after transplantation, and to examine the underlying mechanisms responsible for the deleterious effects of IRI. Furthermore, we propose to show that mitochondrial-targeted therapies, which have already been shown to be safe in humans in non-transplant settings, can improve long term graft outcomes after transplantation. It is hoped that this study will facilitate the timely and efficient introduction of these therapies into clinical practice.