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性

• 批准号: 8466120
• 负责人: STEVEN A. WEBBER
• 金额: $ 117.42万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/8466120
• 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; Devices; 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; 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

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，很少有接受者生存超过20年。由于围手术期死亡率降低，早期结果得到改善，早期急性排斥反应发生率也有所下降。然而，持续的移植物丢失在第一年后以每年2-3%的稳定状态发生，“慢性排斥”是晚期移植物丢失的最常见原因。目前的药物治疗方案在预防急性排斥反应方面是有效的，但在预防移植物血管病变方面似乎基本无效。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。一个新兴的文献表明，供体特异性HLA抗体（DSA）是慢性移植物丢失的关键驱动因素，并且不粘附可能在其发展中起重要作用。也有越来越多的文献表明，对自身抗原的免疫在移植物血管病变的发展中起着重要作用，尽管这还没有在儿童中进行过研究。我们的目标是解决同种免疫，自身免疫和不遵守之间的复杂的相互作用。我们将通过三项相互关联的研究来探讨这些主题。项目1是一项观察性队列研究，旨在确定DSA（预成形与从头）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。将定义结局的风险因素，并评价晚期排斥反应发作的分子病理学。将通过评价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变（小动脉病变）来评估抗体对微血管病理生理学改变发展的影响。创新的多重标记、自动化图像分析和内皮细胞培养模型将用于实现该终点。我们假设，新发DSA将是不良结局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将是一项随机对照试验，研究新型移动终端应用程序（Teen Pocket PATH）改善11岁以上儿童心脏移植后的依从性。我们假设，干预措施将改善药物依从性，并将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产生减少。项目3将是一项II期非随机、开放标签试验，评价基于硼替佐米的方案对高度致敏的儿科心脏移植候选人进行脱敏，以评估该方案在儿科人群中的安全性，并通过评价计算的PRA、抗体强度和补体结合能力/IgG亚类以及治疗前与治疗后血清中与供体交叉配型阴性的患者比例来评估疗效。我们假设，硼替佐米为基础的方案将有效地减少抗HLA抗体和减少计算的PRA。