Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery

项目概述：面部和肢体血管化复合同种异体移植（VCA）移植（Tx）不仅是 可行，但可以是恢复复杂结构的美学和功能的上级方法。尽管 尽管最近在VCA Tx的技术方面取得了长足进步，但仍然迫切需要开发新的 改善移植物功能和存活的方法。然而，VCA产生强烈的免疫反应， 并且接受者需要终身的积极免疫抑制以防止排斥。这将收件人置于 由于免疫抑制药物的高毒性，存在相当大的风险和缩短的预期寿命。值得注意的是， 免疫抑制剂具有神经毒性，可损害神经再生，导致移植物质量下降 功能恢复鉴于此，并且由于VCA Tx通常会改变生活，但不会挽救生命，因此原则 研究目标，也是本文所讨论的一个目标，是开发新的策略，不仅促进 免疫抑制保留方案的使用还使得神经发生和移植物功能恢复成为可能。 虽然T细胞介导的排斥反应是移植物排斥反应的核心，但实体器官移植（SOT）的研究已经确定， 移植后早期脑死亡（BD）诱导的损伤和缺血再灌注损伤（IRI）， 作为同种免疫反应的关键引物。BD和IRI是否在VCA中扮演类似的角色， 研究了BD和IRI都是VCA Tx过程中不可避免的早期事件。我们建议调查 这些急性移植前和移植后损伤对同种免疫反应形成的作用， 其对移植物排斥、功能恢复和免疫抑制剂剂量的影响， 防止T细胞介导的排斥反应。我们的工作假设是，减少BD诱导的损伤和IRI将减少 移植物的同种异体反应性和改善神经再生和修复，从而使更广泛的 这一改变人生的过程。具体来说，我们将：1。描述一种新的靶向方法， 将补体抑制剂递送至VCA，和2.确定BD、C和早期同种异体移植物损伤在 急性同种免疫反应、所需免疫抑制治疗的参数和功能性后肢 复苏这项提议的潜在影响是深远的，因为成功减少了早期移植物损伤， 排斥反应在促进功能恢复的同时，有可能扩大这种改变生活的方法的利用。 procedure.此外，研究的治疗方法和获得的机制见解可能会 对多种移植程序的影响。

Project Summary: Face and limb vascularized composite allograft (VCA) transplantation (Tx) is not only feasible, but can be a superior method of restoring the aesthetics and function of complex structures. Despite the recent strides made in the technical aspects of VCA Tx, there is still an urgent need to develop novel approaches to improve graft function and survival. However, VCAs generate a strong immunological response, and recipients require life-long aggressive immunosuppression to prevent rejection. This places the recipient at substantial risk and shortened life expectancy due to the high toxicity of immunosuppressive drugs. Significantly, immunosuppressives are neurotoxic and can impair neuroregeneration, leading to poorer graft functional recovery. Given this, and because VCA Tx is usually life-changing, but not lifesaving, a principle research goal, and one that is addressed herein, is the development of novel strategies that not only facilitate the use of immunosuppressive sparing regimes but also enable neurogenesis and graft functional recovery. While T cell-mediated rejection is central to graft rejection, studies in solid organ transplant (SOT) have identified the early post-transplant graft injuries of brain death (BD) induced injury and ischemia reperfusion injury (IRI), as key primers of the alloimmune response. Whether BD and IRI play similar roles in VCA has not been investigated. Both BD and IRI are unavoidable early events in the VCA Tx process. We propose to investigate the role of these acute pre and post-transplant injuries on the shaping of an alloimmune response and the consequences thereof on graft rejection, functional recovery, and dose of immunosuppressive required to prevent T-cell mediated rejection. Our working hypothesis is that reducing BD induced injury and IRI will reduce graft alloresponsiveness and improve nerve regeneration and repair, thus enabling the more widespread application of this life-changing procedure. Specifically, we will: 1. Characterize a novel targeting approach for delivery of a complement inhibitor to VCAs, and 2. Determine the role of BD, C and early allograft injury on an acute alloimmune response, the parameters of required immunosuppressive therapy, and functional hindlimb recovery. The potential impact of this proposal is far-reaching as success in reducing early graft injury and rejection, while promoting functional recovery, has the potential to expand the utilization of this life changing procedure. Furthermore, the therapeutic approaches investigated and mechanistic insights gained will likely have implications for multiple transplantation procedures.