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疗法，很少有接受者能够存活超过 20 年。由于围手术期死亡率降低，早期结果有所改善，早期急性排斥反应率也有所下降。然而，第一年后，持续的移植物损失以每年 2-3% 的稳定状态发生，“慢性排斥”是晚期移植物损失的最常见原因。目前的药物治疗方案可有效预防急性排斥反应，但在预防移植物血管病变方面似乎基本上无效。我们未能在这一领域取得进展反映出我们对导致这一严重并发症的机制的无知。一项新兴文献表明，供体特异性 HLA 抗体 (DSA) 是慢性移植物丢失的关键驱动因素，而不依从性可能在其发展中发挥重要作用。还有越来越多的文献表明，对自身抗原的免疫在移植血管病变的发展中发挥着重要作用，尽管尚未在儿童中进行研究。我们的目标是解决同种免疫、自身免疫和不依从性之间复杂的相互作用。我们将通过三项相互关联的研究来解决这些主题。项目 1 是一项观察性队列研究，旨在确定 DSA（预先形成与从头形成）和自身抗原抗体（心肌肌球蛋白、波形蛋白）对慢性移植物功能的长期影响。我们还将评估同种抗体和自身抗体对晚期（>1年）严重不良事件发生率的影响，包括死亡、急性排斥反应和急性移植物功能障碍。将定义结果的危险因素，并评估晚期排斥反应的分子病理学。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（动脉病）来评估抗体对改变的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实现这一终点。我们假设从头 DSA 将是不良后果和微血管病变发展的最强预测因子，而不依从性将导致这种并发症。项目 2 将是一项新型移动设备应用程序 (Teen Pocket PATH) 的随机对照试验，旨在提高 11 岁以上儿童心脏移植后的依从性。我们假设干预措施将提高药物依从性并减少急性排斥反应事件。我们还假设这将导致同种抗体和自身抗体的从头生产减少。项目 3 将是一项基于硼替佐米的方案的 II 期非随机、开放标签试验，用于对高度敏感的儿科心脏移植候选者进行脱敏，以评估该方案在儿科人群中的安全性，并通过评估计算的 PRA 来评估疗效，抗体强度和补体固定能力/IgG亚类以及在治疗前与治疗后血清中与供体交叉匹配呈阴性的患者比例。我们假设基于硼替佐米的治疗方案将有效减少抗 HLA 抗体并减少计算的 PRA。