Improving transplant organ survival through the mitigation of donor-derived mitochondrial damage-associated molecular patterns

移植的需求大大超过了器官的可获得性，而且超过30,000个固体器官中的许多 在美国每年进行的移植(移植物)将在5年内丢失-主要是由于 免疫介导的移植物排斥反应。因此，迫切需要改进减少贪污的办法。 排斥反应和扩大可用器官池。一种减少排斥和改善移植物的新策略 质量是为了减轻移植前发生的移植物损伤。大多数移植器官来自 已故捐赠者，与活体捐赠者的器官相比，结果较差。这种差异 据信是移植物损伤和免疫原性增加的结果，这是由以下原因引起的炎症 脑死亡。这项拟议研究的基本原理是识别特定的细胞和分子 促进已故器官捐赠者移植排斥反应的途径将导致新的 移植前提高器官质量的方法。现在已经知道线粒体释放到细胞内 脑死亡后的循环是无菌炎症的有力刺激因素，并促进移植物功能障碍和 拒绝。这项提案的总体目标是定义特定的线粒体衍生损伤 导致移植物损伤的相关分子模式(MtDAMPs)，并开发缓解方法 MtDAMP诱导的炎症反应，以提高移植前的移植质量。中心假说 通过减少移植物炎症和减少移植器官的存活，可以改善移植器官的功能和存活率 已故供者的循环线粒体引起的损伤。以强大的初步数据为指导，并使用 结合动物模型和人体组织，将通过完成三项假设来验证这一假设 具体目标：1)确定增加器官排斥反应的mtDAMPs；2)确定 在机器灌流过程中抑制mtDAMPs对移植物保存和移植后功能的影响； 评估mtDAMP靶向治疗在机器灌流过程中减少人类肾脏损伤的能力。 通过完成这项提案的目标而获得的结果将是重要的，因为它们将确定 导致已故器官捐赠者和体外炎症的特定先天免疫途径 灌流。这一知识将加速开发消除这些疾病的候选疗法。 移植前的反应和减轻移植物损伤，从而扩大器官利用和改善器官 质量。将移植前作为减少移植后免疫反应的一种策略 降低排斥率或提高体外器官质量是创新的，代表了 旨在改善移植结果的战略。通过完成这个项目所获得的知识 将为支持包括人体临床试验在内的后续研究提供基础，并实现长期目标 开发干预措施，通过改善供体来提高器官移植的临床成功率 器官质量。

The need for transplantation vastly exceeds organ availability, and many of the over 30,000 solid organ transplants (grafts) performed in the United States annually will be lost within 5 years —primarily as a result of immune-mediated graft rejection. Thus, there is a critical need for improved approaches to reduce graft rejection and to expand the pool of usable organs. A novel strategy for reducing rejection and improving graft quality is to mitigate graft injury occurring prior to transplantation. The majority of transplant organs are from deceased donors, which have inferior outcomes when compared to organs from living donors. This difference is believed to be a result of increased graft injury and immunogenicity caused by inflammation resulting from brain death. The rationale for the proposed research is that identifying the specific cellular and molecular pathways that promote graft rejection in deceased organ donors will lead to the development of novel approaches to improve organ quality prior to transplant. It is now known that mitochondria released into the circulation after brain death are potent stimulators of sterile inflammation and promote graft dysfunction and rejection. The overall objectives of this proposal are to define the specific mitochondria-derived damage associated molecular patterns (mtDAMPs) that cause graft injury, and to develop methods to mitigate mtDAMP-induced inflammation in order to improve graft quality prior to transplantation. The central hypothesis is that the function and survival of transplanted organs can be improved by reducing graft inflammation and injury caused by circulating mitochondria in deceased donors. Guided by strong preliminary data, and using a combination of animal models and human tissues, the hypothesis will be tested through completion of three Specific Aims: 1) Identify the mtDAMPs responsible for increasing organ rejection; 2) Determine the effect of inhibiting mtDAMPs during machine perfusion on graft preservation and post-transplant graft function; and 3) Evaluate the ability of mtDAMP-targeting therapies to reduce human kidney injury during machine perfusion. The results obtained by completing the aims of this proposal will be significant because they will identify specific innate immune pathways responsible for inflammation in deceased organ donors and during ex vivo perfusion. This knowledge will accelerate the development of candidate therapies for abrogating these responses and mitigating graft injury prior to transplant, thus expanding organ utilization and improving organ quality. Treating grafts pre-implantation as a strategy to reduce immune responses following transplant and reduce rates of rejection, or to improve organ quality ex vivo, is innovative, and represents a paradigm shift for strategies aimed at improving transplant outcomes. The knowledge gained though completion of this project will provide a foundation to support subsequent studies, including human clinical trials, with the long-term goal of developing interventions that increase the clinical success of organ transplantation by improving donor organ quality.