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

脑死亡相关血管化复合同种异体移植物损伤及其对同种免疫和功能恢复的影响

• 批准号: 10399007
• 负责人: Carl Atkinson
• 金额: $ 33.78万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399007
• 关键词: Acute; Address; Adhesions; Allografting; Antibodies; Blood Vessels; Brain Death; Brain Injuries; Brain Ischemia; Cell Adhesion Molecules; Cell Communication; Cells; Climacteric; Coagulation Process; Complement; Complement Activation; Complement Inactivators; Complex; Cyclosporine; Data; Deposition; Development; Dose; Endothelial Cells; Endothelium; Esthetics; Event; Face; Goals; Graft Rejection; Graft Survival; Hindlimb; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Impairment; Inflammation; Injury; Intercellular adhesion molecule 1; Leukocytes; Life; Life Expectancy; Limb structure; Link; Longevity; Mediating; Methods; Modeling; Muscle; Natural regeneration; Nerve; Nerve Degeneration; Nerve Regeneration; Nervous System Trauma; Organ Transplantation; P-Selectin; Patients; Pharmaceutical Preparations; Platelet aggregation; Play; Prevention; Procedures; Process; Recovery; Recovery of Function; Reperfusion Injury; Research; Rest; Risk; Role; Savings; Shapes; Skin; Solid; Structure; System; T-Lymphocyte; Tacrolimus; Therapeutic; Therapeutic immunosuppression; Thrombosis; Time; Toxic effect; Transplantation; allograft rejection; bone; central nervous system injury; complement pathway; complement system; congenic; graft function; high risk; improved; inhibitor/antagonist; innovation; insight; isoimmunity; nerve repair; neurogenesis; neurotoxic; novel; novel strategies; novel therapeutic intervention; peripheral nerve repair; post-transplant; prevent; response; success; tool; transplant model; transplantation therapy

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.

项目摘要：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优越方法。尽管 最近在VCA TX的技术方面取得了进步，仍有迫切需要开发小说 改善移植功能和生存的方法。但是，VCA产生强烈的免疫反应， 接收者需要终身侵略性免疫抑制以防止排斥。这使收件人处于 由于免疫抑制药物的毒性高，因此很大的风险和预期寿命缩短。显著地， 免疫抑制剂是神经毒性的，可能会损害神经因子，导致移植物较差 功能恢复。鉴于此，并且由于VCA TX通常改变生活，但不是救生，所以 研究目标以及本文所解决的目标是发展新型策略，不仅有助于 使用免疫抑制性的节省方案，还可以实现神经发生和移植功能恢复。 尽管T细胞介导的排斥反应是移植排斥的核心，但固体器官移植（SOT）的研究已经鉴定 脑死亡（BD）造成损伤和缺血再灌注损伤（IRI）的早期移植后移植物伤害（IRI）， 作为同种免疫反应的关键引物。 BD和IRI在VCA中是否扮演类似的角色 调查。在VCA TX过程中，BD和IRI都是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伤害的作用在同种免疫反应的塑造和 在移植排斥，功能恢复和免疫抑制剂量上，其后果需要 防止T细胞介导的排斥。我们的工作假设是减少BD诱导的损伤和IRI会减少 移植物同种异体并改善神经再生和修复，从而使能力更广泛 改变这种改变生活的程序。具体来说，我们将：1。表征一种新颖的靶向方法 将补体抑制剂递送至VCA，2。确定BD，C和早期同种异体损伤对 急性同种免疫反应，所需的免疫抑制疗法的参数和功能性后肢 恢复。该提案的潜在影响是在减少早期移植损伤和 拒绝同时促进功能恢复，有可能扩大这种生活的利用 程序。此外，所研究的治疗方法和获得的机理见解可能会有 对多个移植程序的影响。