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

描述(申请人提供)：心脏移植仍然是一种姑息疗法，很少有接受者能存活20年以上。随着围手术期死亡率的降低，早期结果有所改善，早期急性排斥率也有所下降。然而，持续的移植物丢失发生在每年2-3%的稳定状态下，在第一年后，‘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大多无效。我们未能在这一领域取得进展，反映了我们对导致这一严重复杂情况的机制的无知。一项新的文献表明，供者特异性的人类白细胞抗原抗体(DSA)是慢性移植物丢失的关键驱动因素，而不黏附可能在它们的发展中起着重要作用。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，尽管这一点尚未在儿童中进行研究。我们的目标是解决同种异体免疫、自身免疫和不粘连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是一项观察性队列研究，旨在确定DSA(预先形成的与从头形成的)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。我们还将评估异体抗体和自身抗体对晚期(&gt；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。将定义影响预后的危险因素，并评估晚期排斥事件的分子病理学。抗体对微血管病理生理学改变的影响将通过评估内皮细胞结构和信号、间质毛细血管网络和闭塞性微血管病变(动脉病变)来评估。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，而不坚持将导致这一并发症。项目2将对一种新型移动设备应用程序(Teen Pocket Path)进行随机对照试验，以提高11岁以上儿童心脏移植后的依从性。我们假设，干预将改善药物依从性，并将减少急性排斥事件。我们还假设，这将导致异体抗体和自身抗体的从头产生减少。项目3将是基于Bortezomib的方案的第二阶段非随机开放标签试验，用于高度致敏的儿童心脏移植候选患者的脱敏，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、抗体强度和补体固定能力/免疫球蛋白G亚类和治疗前后血清与供者交叉匹配阴性的患者比例来评估疗效。我们推测，基于硼替佐米的治疗方案将有效地降低抗人类白细胞抗原抗体，并减少计算的PRA。

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.