Chronic Graft Destruction: Interplay of Allo- and Autoantibodies and Nonadherence

慢性移植物破坏：同种抗体和自身抗体的相互作用以及不依从

基本信息

批准号：
8606403
负责人：
STEVEN A. WEBBER
金额：
$ 84.55万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606403
关键词：
11 year old 21 year old Acute Address Adherence Adverse event Aftercare Allografting Angiography Antibodies Antibody Formation Apoptotic Area Autoantibodies Autoantigens Autoimmunity Automobile Driving Blood capillaries Bortezomib Brain natriuretic peptide Cardiac Myosins Cell Culture Techniques Cellular Structures Cessation of life Child Childhood Chronic Clinical Cohort Studies Complement Complex Complication Coronary Coronary heart disease Development Donor Selection Echocardiography Endothelial Cells Evaluation Event Failure Functional disorder Heart Heart Transplantation Heart failure Image Analysis Immunity Immunoglobulin G Incidence Intervention Isoantibodies Label Laboratories Lead Literature Mediating Medical Modeling N-terminal Outcome Palliative Care Patients Perioperative Pharmaceutical Preparations Phase Play Population Production Protocols documentation Randomized Controlled Trials Recurrence Regimen Risk Factors Role Safety Secondary to Serious Adverse Event Serum Signal Transduction Staging Technology Teenagers Transplantation Vascular Diseases Vimentin adverse outcome base capillary cohort cytotoxicity desensitization falls graft function handheld mobile device hazard heme oxygenase-1 hemodynamics improved innovation interstitial intervention effect isoimmunity molecular pathology mortality novel open label outcome forecast palliative prevent progenitor public health relevance randomized trial senescence

项目摘要

DESCRIPTION (provided by applicant): Heart transplantation remains a palliative therapy with few recipients achieving survival beyond 20 years. Early results have improved secondary to reductions in perioperative mortality and early acute rejection rates have also fallen. However, ongoing graft loss occurs at a steady state of 2-3% per year after the first year with 'chronic rejection' being the commonest cause of late graft loss. Current medication regimens are effective at preventing acute rejection but appear to be largely ineffective at preventing graft vasculopathy. Our failure to make strides in this area reflects our ignorance of the mechanisms driving this serious complication. An emerging literature suggests that donor-specific HLA antibodies (DSA) are key drivers of chronic graft loss, and nonadherence may play an important role in their development. There is also a mounting body of literature to suggest that immunity to self-antigens plays an important role in the development of graft vasculopathy, though this has not been studied in children. We aim to address the complex interplay between alloimmunity, autoimmunity and nonadherence. We will address these themes through three interrelated studies. Project 1 is an observational cohort study to determine the long-term impact of DSA (preformed versus de novo) and antibodies to self-antigens (cardiac myosin, vimentin) on chronic graft function. We will also evaluate the impact of allo- and autoantibodies on the incidence of late (>1 year) serious adverse events including death, acute rejection, and acute graft dysfunction. Risk factors for outcomes will be defined, and the molecular pathology of late rejection episodes will be evaluated. The impact of antibodies on the development of altered microvascular pathophysiology will be assessed through evaluation of endothelial cell structure and signaling, interstitial capillary network and obliterative microvasculopathy (arteriolopathy). Innovative multiplex labeling, automated image analysis and endothelial cell culture models will be used to accomplish this endpoint. We hypothesize that de novo DSA will be the strongest predictors of adverse outcomes and development of microvasculopathy and that nonadherence will drive this complication. Project 2 will be a randomized, controlled trial of a novel mobile device application (Teen Pocket PATH) to improve adherence in children greater than 11 years of age after heart transplantation. We hypothesize that the intervention will improve adherence to medications and will reduce acute rejection events. We also hypothesize that this will lead to less de novo production of allo- and autoantibodies. Project 3 will be a phase II non-randomized, open label trial of a bortezomib-based regimen for desensitization of highly sensitized pediatric heart transplant candidates to assess the safety of the regimen in a pediatric population and to assess efficacy via evaluation of calculated PRA, antibody strength and complement fixing ability/IgG subclass and proportion of patients with negative cross-match against donor on pre- versus post-treatment sera. We hypothesize that a bortezomib-based regimen will be effective in reducing anti-HLA antibodies and reducing calculated PRA.

描述（由申请人提供）：心脏移植仍然是一种姑息治疗，很少有人能够在20年以后获得生存。早期结果改善了围手术期死亡率降低的继发性和早期急性排斥率也下降了。然而，第一年后，持续的移植物损失每年的稳态损失为每年2-3％，“慢性拒绝”是最常见的移植物损失原因。当前的药物治疗方案可有效预防急性排斥反应，但在预防移植血管病中似乎在很大程度上无效。我们未能在这一领域取得进步，这反映了我们对驱动这种严重并发症的机制的无知。新兴文献表明，特异性HLA抗体（DSA）是慢性移植损失的关键驱动因素，不遵守可能在其发展中起重要作用。还有一系列文献表明，对自我抗原的免疫力在移植血管病的发展中起着重要作用，尽管这尚未在儿童中进行研究。我们旨在解决同种免疫，自身免疫和不遵守之间的复杂相互作用。我们将通过三个相互关联的研究来解决这些主题。项目1是一项观察队列研究，旨在确定DSA（预成型与从头开始）和对自我抗原（心脏肌球蛋白，Vimentin）对慢性移植功能的长期影响。我们还将评估同种和自身抗体对（> 1年）严重不良事件发生率（包括死亡，急性排斥和急性移植功能障碍）发生率的影响。将定义结果的危险因素，并将评估后期排斥发作的分子病理。将通过评估内皮细胞结构和信号传导，间质毛细血管网络和闭塞性微血管病病（动脉炎）来评估抗体对改变微血管病理生理学发展的影响。创新的多重标记，自动图像分析和内皮细胞培养模型将用于完成此终点。我们假设从头DSA将是不良后果和微堡病发展的最强大预测指标，而不遵守会导致这种并发症。项目2将是一项新型移动设备应用程序（青少年口袋路径）的随机对照试验，以提高心脏移植后11岁以上儿童的依从性。我们假设干预将提高对药物的依从性，并减少急性排斥事件。我们还假设这将导致从头产生同种和自身抗体的生产。 Project 3 will be a phase II non-randomized, open label trial of a bortezomib-based regimen for desensitization of highly sensitized pediatric heart transplant candidates to assess the safety of the regimen in a pediatric population and to assess efficacy via evaluation of calculated PRA, antibody strength and complement fixing ability/IgG subclass and proportion of patients with negative cross-match against donor on pre- versus治疗后血清。我们假设基于硼替佐米的方案将有效减少抗HLA抗体并减少计算出的PRA。