Epitope mismatch and medication nonadherence

 描述（由申请人提供）：在过去的30年中，我们已经看到1年肾移植患者和移植物存活率的显著改善，但长期结局的改善有限。迄今为止，成功主要是由于更有效的免疫抑制治疗，允许在肾脏分配中不强调HLA配型。然而，免疫应答的激活（通过急性排斥反应和/或新发供体特异性抗体的发展可见）继续在晚期移植物丢失中起主要作用。最近的研究表明，表位不匹配和药物不依从是导致急性排斥反应、新的供体特异性抗体和晚期移植物丢失的两个因素。遗传和蛋白质建模的进展目前允许更详细地比较供体和受体HLA分子之间的相似性和差异。这些新技术能够研究表位（分子的亚部分）而不是整个HLA分子，并确定移植供体和受体之间是否存在表位匹配。在独立的研究中，我们发现表位错配和亚临床（临床上没有意识到，只能通过电子监测检测到）药物治疗不依从性都与肾移植结局恶化相关。我们的初步数据表明，它们是独立的，协同的，相关的晚期排斥反应和移植物丢失。为了准备R34补助金，我们组建了一个国际多学科团队，在肾移植临床试验，药物不依从性（特别是移植药物不依从性）和转化人类免疫学研究方面具有丰富的经验。该试验将在8个承诺的北美中心进行。R34补助金的目标是制定并最终确定一项为期5年的研究提案。5年资助的目标是：（1）在一个前瞻性的、遗传多样性的“真实的世界”队列中，确定表位错配和早期亚临床药物不依从性对从头供体特异性抗体、急性排斥、移植物功能障碍和移植物丢失的发展的独立和协同影响;（2）确定是否存在特异性免疫显性表位错配，而与受体的种族无关;以及（3）在对早期亚临床免疫缺陷的受体的前瞻性随机对照研究中， 药物不依从性，改善后续依从性的干预是否可以减轻早期不依从性和/或表位不匹配对移植结果的影响。我们的研究将是第一个关于移植受者表位错配和亚临床药物治疗不依从性的前瞻性研究。这将是第一个确定，在那些不遵守（一个亚组， 晚期排斥和移植物丢失的高风险组），如果多组分干预是可扩展的并且可能适用于临床使用，将减少持续的药物不依从性，改变早期药物不依从性的影响（有或没有表位错配）并改善临床结果。这些研究的结果可能会影响肾脏分配算法和移植后临床护理。

 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.