Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation

摘要：器官移植是器官衰竭患者的主流治疗方法;然而，尽管 虽然该领域取得了重大进展，但移植的两个主要组成部分进展甚微， 器官保存和维持免疫抑制。免疫抑制治疗虽然必要， 具有显著的副作用负担，经常导致患者死亡和移植失败。此外，该过程 器官获取的最常见的方法是使用脑死亡捐赠者的移植物， 将器官保存在储存溶液中。在这些事件中，器官中的内皮细胞（EC） 同种异体移植物在免疫学上被致敏，然后经受再灌注损伤。早期的创伤 易使EC发生不适当的抗原呈递和慢性移植物功能障碍的影响，包括移植物 血管病变导致长期移植失败。低温保存改变了 同种异体移植物，这反过来又被假设改变了EC的免疫原性，最终影响细胞的免疫原性。 功能性成果。这一级联反应的核心是线粒体在塑造免疫代谢过程中的作用。 同种异体移植物在冷缺血和再灌注损伤中的环境。在这份提案中，我们首次， 探讨线粒体形态与免疫代谢之间的机制关系， 内皮细胞及其在移植环境中的免疫原性。我们根据自己的数据来评估 保存过程中线粒体超微结构变化对EC免疫原性的影响 移植阶段。我们认为，通过抑制内皮细胞的早期免疫原性作用，我们可以创造 使用减少的免疫抑制方案诱导同种异体移植物耐受的机会， 减少这些必需药物的有害后果。我们将采用科学的前提， 通过改变其代谢核心将EC重编程为更具致耐受性的状态，使得其诱导耐受性的能力降低。 同种异体反应性T细胞的促炎性变化减少。使用临床相关的体内模型， 因此，我们预期改变EC线粒体将改善移植物存活并消除病理学 与同种异体移植排斥反应有关。以我们的初步数据为基础，我们假设冷缺血 通过改变线粒体形态加剧EC的免疫原性能力和代谢谱 导致同种异体移植物损伤。此外，我们的目标是保护器官移植物， 使EC偏向更耐受性的表型。 目标1.我们将确定器官保存过程中线粒体形态对 内皮细胞的免疫原性。 目标二。我们的目的是评估线粒体形态对缺血再灌注损伤的影响 和体内急性移植排斥反应。 用线粒体融合疗法进行预治疗将改变目前移植中的护理标准。

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.