Alloantibodies in Cardiac Transplantation - Intervention, Outcomes and Mechanisms

心脏移植中的同种抗体 - 干预、结果和机制

• 批准号: 7914250
• 负责人: STEVEN A. WEBBER
• 金额: $ 120.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914250
• 关键词: Acute; Address; Adult; Allografting; Antibodies; Antibody Specificity; Antigens; Apoptotic; Binding; Biological Assay; Biological Markers; Blood Component Removal; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Childhood; Chimerism; Chronic; Clinical Trials; Complement; Complement Activation; Complement-Dependent Cytotoxicity; Coronary Arteriosclerosis; Development; Economics; Endothelial Cells; Enrollment; Enzyme-Linked Immunosorbent Assay; Evaluation; Exposure to; Functional disorder; Future; Gene Activation; Globulins; Graft Rejection; Health Status; Heart Transplantation; Human; Immune response; Immunosuppressive Agents; Injury; Intervention; Intravenous Immunoglobulins; Isoantibodies; Knowledge; Lead; Measurement; Mediating; Mediator of activation protein; Observational Study; Outcome; Pathway interactions; Patients; Phase; Phenotype; Plasma Exchange; Plasmapheresis; Population; Postoperative Period; Prevalence; Protocols documentation; Randomized; Regimen; Research Personnel; Resistance; Risk; Risk Factors; Safety; Sampling; Scientist; Screening procedure; Solid; Specificity; T-Lymphocyte; Time; Transplant Recipients; Transplantation; Vascular Endothelial Cell; Waiting Lists; activation product; arm; base; blood product; cohort; cytotoxicity; design; hemodynamics; improved; mortality; novel; palliative; prospective; response; social; treatment trial

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.

描述（由申请人提供）： 描述（由申请人提供）： 针对同种异体移植抗原的抗体越来越被认为是成人同种异体移植结果的关键决定因素。儿科心脏移植候选者经常因之前接触血液制品和同种移植物而出现异体过敏。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针对供体特异性交叉配血的移植，并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，研究预制和从头同种抗体对儿科心脏移植结果的影响。具体目标 1 将确定 380 名儿科移植候选者的连续队列中抗 HLA 和 MICA 同种抗体的流行率、滴度和抗原特异性。将确定其发展的风险因素。具有预先形成的抗 HLA 抗体和阳性供体特异性交叉配型的候选人将进入多中心、非随机治疗试验，以评估统一管理方案的安全性和有效性（具体目标 2）。该方案将涉及术中和术后血浆置换/血浆置换以及统一的免疫抑制方案。主要终点是移植后一年内没有死亡、移植物丢失和排斥反应且血流动力学受损的患者比例。我们假设 75% 的患者将达到这一终点。非致敏候选者将在统一免疫抑制方案（具体目标 3）下的前瞻性观察方案中进行研究，以确定从头抗 HLA 和抗 MICA 抗体的流行率。我们假设从头抗体的产生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会出现移植物损伤，而另一些儿童似乎在存在阳性供体特异性交叉配型的情况下“适应”他们的移植物。我们假设三个相互关联的因素有助于移植物适应：1）。抗体的特征2)。内皮细胞对抗体介导的损伤的抵抗力和3)。用受体来源的血管内皮细胞替换供体血管内皮细胞，导致内皮嵌合。最后，我们将研究开发一种非侵入性体液排斥标记物；细胞结合补体激活产物的定量测量。 CTOT-C 为执行所提出的研究提供了理想的机制，并且应该带来关于儿科心脏移植中抗体介导的移植物损伤的重要新知识。它应该为该领域未来临床试验的设计提供急需的信息。相关性：小儿心脏移植仍然是姑息治疗，对再移植的需求很高，经济和社会负担也很大。所有能够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，并减轻有限捐赠者库的负担。