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: 10293947
• 负责人: Carl Atkinson
• 金额: $ 7.47万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293947
• 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.

项目概要：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观和功能的更好方法。尽管 尽管最近在 VCA Tx 技术方面取得了长足的进步，但仍然迫切需要开发新颖的 改善移植物功能和存活率的方法。然而，VCA 会产生强烈的免疫反应， 接受者需要终生积极的免疫抑制以防止排斥。这将接收者置于 由于免疫抑制药物的高毒性，存在巨大的风险并缩短预期寿命。显著地， 免疫抑制剂具有神经毒性，会损害神经再生，导致移植效果较差 功能恢复。鉴于此，并且由于 VCA Tx 通常可以改变生活，但不能挽救生命，因此有一个原则 研究目标，也是本文所讨论的一个，是开发新的策略，不仅促进 使用免疫抑制保留方案还可以实现神经发生和移植物功能恢复。 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) 的研究已经发现 移植后早期的脑死亡（BD）损伤和缺血再灌注损伤（IRI）损伤， 作为同种免疫反应的关键引物。 BD 和 IRI 在 VCA 中是否扮演相似的角色尚未得到证实。 调查了。 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以及 其对移植物排斥、功能恢复和所需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 引起的损伤和 IRI 将减少 移植物同种异体反应性并改善神经再生和修复，从而使更广泛的 应用这一改变生活的程序。具体来说，我们将： 1. 描述一种新颖的靶向方法 向 VCA 递送补体抑制剂，以及 2. 确定 BD、C 和早期同种异体移植物损伤对 急性同种免疫反应、所需免疫抑制治疗的参数以及后肢功能 恢复。该提案的潜在影响是深远的，因为成功减少了早期移植物损伤和 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用途 程序。此外，所研究的治疗方法和获得的机制见解可能会 对多次移植手术的影响。