Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation

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ABSTRACT: Organ transplantation is a mainstream therapy for patients with organ failure; however, despite major advances in the field, there has been little progress regarding two major components of transplantation -- organ preservation and maintenance immunosuppression. Although essential, immunosuppressive therapy carries a significant side-effect burden, often leading to patient death and graft failure. In addition, the process of organ procurement most often includes use of grafts from brain dead donors followed by hypothermic preservation of the organs in storage solutions. During these events, the endothelial cells (EC) in the organ allografts are primed immunologically and are then subjected to the insults of reperfusion. This early injury predisposes the EC to inappropriate antigen presentation and effects of chronic graft dysfunction, including graft vasculopathy leading to long-term graft failure. Hypothermic preservation changes the metabolism of the allograft, which in turn is hypothesized to alter the immunogenicity of the ECs ultimately affecting cellular functional outcomes. Central to this cascade is the role of the mitochondria in shaping the immunometabolic milieu of the allograft in the face of cold ischemia and reperfusion injury. In this proposal we, for the first time, explore the mechanistic relationship between the mitochondrial morphology and immunometabolism of ECs and their immunogenicity in the setting of transplantation. We build upon our own data to assess the effects of forcing mitochondrial ultrastructural changes on the immunogenic profile of EC during the preservation phase of transplantation. We propose that by dampening the early immunogenic effects of ECs, we can create the opportunity to induce allograft tolerance with the use of reduced immunosuppressive regimens thereby reducing the deleterious consequences of these necessary drugs. We will employ the scientific premise of reprograming ECs to a more tolerogenic state by altering their metabolic core such that their ability to induce proinflammatory changes from alloreactive T cells are diminished. Using clinically relevant in vivo models of transplantation, we anticipate that altering EC mitochondria will improve graft survival and abrogate the pathology associated with allograft rejection. Using our preliminary data as a backbone we hypothesize that cold ischemia exacerbates the immunogenic capacity and metabolic profile of EC by altering mitochondrial morphology resulting in allograft injury. Additionally, with the following aims, our goal will be to protect organ allografts and skew the EC to a more tolerogenic phenotype. Aim 1. We will determine the impact of mitochondrial morphology during organ preservation on the immunogenicity of endothelial cells in vitro. Aim 2. We aim to assess the impact of mitochondrial morphology on ischemia reperfusion injury and acute transplant rejection in vivo. Pre-treatment with mitochondrial fusion therapeutics will shift the current standard of care in transplantation.