Epitope mismatch and medication nonadherence

 描述(由申请人提供)：在过去的30年里，我们看到肾移植患者的一年存活率和移植物存活率有了显著的改善，但长期结果的改善有限。到目前为止，成功在很大程度上是更有效的免疫抑制治疗的结果，允许在肾脏分配中不再强调HLA匹配。然而，免疫反应的激活(通过急性排斥反应和/或新的供者特异性抗体的产生)，继续在晚期移植物丢失中发挥主要作用。最近的数据表明，与急性排斥、新的供者特异性抗体和晚期移植物丢失相关的两个因素是表位不匹配和药物不依从性。目前，在遗传和蛋白质建模方面的进展允许更详细地比较供体和受体之间的相似和不同之处。这些新技术能够研究表位(分子的亚部分)，而不是整个人类白细胞抗原分子，并确定移植供者和接受者之间是否存在表位匹配。在独立的研究中，我们发现表位不匹配和亚临床(临床上没有意识到，只有通过电子监测才能检测到)药物不依从性都与较差的肾脏移植结果相关。我们的初步数据显示，它们是独立的、协同的，与晚期排斥反应和移植物丢失相关。为了准备R34赠款，我们组建了一个国际化的多学科团队，在肾移植临床试验、药物非依从性(特别是移植药物非依从性)和翻译性人类免疫学研究方面拥有丰富的经验。这项试验将在8个承诺的北美中心进行。R34赠款的目标是制定并最终确定一项为期5年的研究计划。这项为期5年的赠款的目标将是：(1)在一个预期的、遗传多样化的“现实世界”队列中，确定表位错配和早期亚临床药物不依从性对新的供者特异性抗体的发展、急性排斥反应、移植物功能障碍和移植物丢失的独立和协同影响；(2)确定是否存在特定的免疫优势表位错配，而不考虑受者的种族；以及(3)在一项针对早期亚临床受者的前瞻性随机对照研究中了解。 药物不依从性，无论是改善后续依从性的干预措施是否减轻早期不依从性和/或表位错配对移植结果的影响。我们将首次对移植受者的表位错配和亚临床用药不依从性进行前瞻性研究。这将是第一个确定那些不遵守的人(一个子组在 如果一种可分级且可能适用于临床的多组分干预措施将减少持续用药不依从，改变早期用药不依从性(有或不存在表位错配)的影响，则可以减少晚期排斥反应和移植物丢失的高危人群)，并改善临床结果。这些研究的结果可能会潜在地影响肾脏分配算法和移植后的临床护理。

 DESCRIPTION (provided by applicant): In the past 3 decades, we have seen significant improvement in 1-year kidney transplant patient and graft survival rates but limited improvement in long-term outcomes. Success, to date, has largely been the result of more potent immunosuppressive therapy that permitted a de-emphasis on HLA matching in kidney allocation. Yet activation of an immune response (seen by development of acute rejection and/or new onset donor specific antibodies), continues to play a major role in late graft loss. Recent data shows that two factors associated with acute rejection, new donor specific antibody and late graft loss are epitope mismatching and medication nonadherence. Advances in genetic and protein modeling currently allow more detailed comparisons of the similarities and differences between donor and recipient HLA molecules. These new techniques are able to study epitopes (sub-sections of the molecule) rather than the entire HLA molecule, and determine whether or not there is epitope matching between the transplant donor and recipient. In independent studies we found that both epitope mismatches and subclinical (not clinically appreciated, and detected only by electronic monitoring) medication nonadherence are each associated with worse kidney transplant outcomes. Our preliminary data shows that they are independent, synergistic, correlates of late rejection and graft loss. For preparation of the R34 grant, we have assembled an international, multidisciplinary team with extensive experience in kidney transplant clinical trials, in medication nonadherence (and specifically in transplant medication nonadherence) and in translational human immunology research. The trial will be done at 8 committed North American centers. The goal of the R34 grant is to develop and finalize a proposal for a 5- year study. The goals of the 5-year grant will be: (1) to determine - n a prospective, genetically diverse "real- world" cohort - the independent and synergistic impact of epitope mismatch and early subclinical medication nonadherence on the development of de novo donor specific antibody, acute rejection, graft dysfunction, and graft loss; (2) to define whether specific immunodominant epitope mismatches exist irrespective of the recipient's race; and (3) to learn, in a prospective randomized controlled study of recipients with early subclinical medication nonadherence, whether intervention to improve subsequent adherence mitigates the impact of early nonadherence and/or epitope mismatches on transplant outcomes. Ours will be the first prospective study of epitope mismatching plus subclinical medication nonadherence in transplant recipients. It will be the first to determine, in those with nonadherence (a subgroup at high risk group for late rejection and graft loss), if a multicomponent intervention that is scalabe and potentially applicable to clinical use, will reduce ongoing medication nonadherence, modify the impact of early medication nonadherence (with or without epitope mismatch) and improve clinical outcomes. The results of these studies could potentially impact both kidney allocation algorithms and postransplant clinical care.