Alloantibodies in Cardiac Transplantation - Intervention, Outcomes and Mechanisms

描述(由申请人提供)：描述(由申请人提供)： 针对同种异体移植物抗原的抗体越来越被认为是成人同种异体移植物结果的关键决定因素。儿科心脏移植候选者经常因先前接触血液产品和同种移植物而被同种异体致敏。为了克服等待名单上的高死亡率，最近在几个儿科中心进行了供者特定交叉配型的移植，取得了令人鼓舞的早期结果。该应用程序汇集了六个领先的心脏移植中心和领先的移植科学家，研究预先形成的和从头开始的同种异体抗体对儿童心脏移植结果的影响。具体目标1将在380名儿科移植候选患者的连续队列中确定抗人类白细胞抗原和MICA同种异体抗体的流行率、效价和抗原特异性。将确定其发展的风险因素。具有预先形成的抗人类白细胞抗原抗体和供者特异性交叉配型阳性的候选人将进入一项多中心、非随机治疗试验，以评估统一治疗方案的安全性和有效性(特定目标2)。该方案将包括术中和术后血浆交换/肾移植和统一的免疫抑制方案。主要终点将是移植后一年内无死亡、移植物丢失和血流动力学损害的排斥反应的患者的比例。我们假设75%的患者将达到这一终点。未致敏的候选人将在统一免疫抑制方案(特定目标3)下进行前瞻性观察方案的研究，以确定从头开始的抗人类白细胞抗原抗体和抗MICA抗体的流行率。我们假设从头抗体的发展将是更频繁和更严重的急性排斥反应的独立预测因素。在具体目标4中，将进行机制研究，以寻求解释为什么一些儿童出现移植物损伤，而另一些儿童似乎在供者特异性交叉配型阳性的情况下‘适应’他们的移植物。我们假设有三个相互关联的因素影响移植物的适应性：1)。抗体特性(S)2)。3)内皮细胞抵抗抗体介导的损伤。用受体来源的血管内皮细胞替换供者血管内皮细胞，导致内皮嵌合体。最后，我们将研究一种非侵入性体液排斥标志物的开发；细胞结合补体激活产物的定量测量。CTOT-C为开展所提出的研究提供了一个理想的机制，并将为儿童心脏移植中抗体介导的移植物损伤带来重要的新知识。它应该为这一领域未来临床试验的设计提供急需的信息。相关性：儿童心脏移植仍然是姑息性的，再次移植的需求很高，经济和社会负担也很大。所有可以提高同种异体移植存活率的策略都将改善这些儿童的健康状况，并将减轻有限的捐赠者池的负担。

DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): Antibodies directed against allograft antigens are being increasingly recognized as critical determinants of allograft outcomes in adults. Pediatric heart transplant candidates are frequently allosensitized based on prior exposure to blood products and homografts. To overcome the high wait-list mortality, transplantation across a donor-specific cross-match has recently been performed in several pediatric centers, with early encouraging results. This application brings together a group of six leading heart transplant centers and leading transplantation scientists to study the impact of preformed and de novo alloantibodies on pediatric heart transplant outcomes. Specific Aim 1 will define the prevalence, titer and antigen specificities of anti- HLA and MICA alloantibodies, in a consecutive cohort of 380 pediatric transplant candidates. Risk factors for their development will be determined. Candidates with preformed anti-HLA antibodies and a positive donor- specific cross-match will enter into a multi-center, non-randomized treatment trial to evaluate the safety and efficacy of a uniform protocol of management (Specific Aim 2). The protocol will involve intra- and post- operative plasma exchange/pheresis and a uniform immunosuppressive protocol. The primary end-point will be the proportion of patients who are free of death, graft loss and rejection with hemodynamic compromise at one year after transplantation. We hypothesize that 75% of patients will achieve this end-point. Non- sensitized candidates will be studied within a prospective observational protocol under a uniform immunosuppressive regimen (Specific Aim 3) to determine the prevalence of de novo anti-HLA and anti- MICA antibodies. We hypothesize that the development of de novo antibodies will be an independent predictor of more frequent and severe acute rejections. In Specific Aim 4, mechanistic studies will be performed to seek explanation for why some children develop graft injury while others appear to 'accommodate' their graft in the presence of a positive donor-specific cross-match. We hypothesize that three interrelated factors contribute to graft accommodation: 1). Characteristics of the antibody(s) 2). Endothelial cell resistance to antibody mediated damage and 3). Replacement of donor vascular endothelial cells with those of recipient origin leading to endothelial chimerism. Finally, we will investigate the development of a non-invasive marker of humoral rejection; quantitative measurement of cell bound complement activation products. The CTOT-C provides an ideal mechanism for performing the proposed studies and should lead to important new knowledge about antibody mediated graft injury in pediatric heart transplantation. It should provide much needed information for the design of future clinical trials in this field. Relevance: Pediatric heart transplantation remains palliative with high demand for re-transplantation and great economic and social burden. All strategies that could enhance allograft survival will improve the health status of these children and will relieve the burden on the limited donor pool.