Epitope mismatch and medication nonadherence

表位错配和药物不依从

基本信息

批准号：
9137126
负责人：
ARTHUR J MATAS
金额：
$ 24.52万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137126
关键词：
Acute Address Adherence Affect Algorithms American Antibodies B-Lymphocytes Case Report Form Cells Cessation of life Chronic Disease Clinical Clinical Trials Clinical Trials Design Clinical trial protocol document Complement Consent Forms Data Databases Development Development Plans Donor person Dose Electronics Enrollment Epitopes Feedback Functional disorder Genetic Goals Graft Rejection Graft Survival Grant HLA Antigens Human Immune Immune response Immunodominant Epitopes Immunology Immunosuppression Immunosuppressive Agents Institutional Review Boards International Intervention Kidney Kidney Transplantation Lead Learning Manuals Modeling Monitor Motion Outcome Pathway interactions Patients Pharmaceutical Preparations Play Preparation Procedures Prospective Studies Proteins Race Randomized Randomized Controlled Trials Research Research Personnel Role Self Care Statistical Data Interpretation Subgroup Survival Rate Techniques Therapeutic immunosuppression Time Training Transplant Recipients Transplantation allograft rejection clinical care clinically relevant cohort design experience high risk improved innovation isoimmunity multi-component intervention multidisciplinary novel operation personalized medicine programs prospective public health relevance randomized trial sample collection screening standard of care success tool

项目摘要

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.

描述（由适用提供）：在过去的三十年中，我们看到了1年肾脏移植患者和谷物存活率的显着改善，但长期结局的改善有限。迄今为止，成功基本上是由于肾脏分配中HLA匹配的强调，这在很大程度上取决于潜在的免疫抑制疗法。然而，激活免疫激素（请参阅急性排斥和/或新发作供体特异性抗体的开发），在晚期谷物损失中继续起主要作用。最近的数据表明，与急性排斥，新的供体特异性抗体和晚期谷物丧失相关的两个因素是表位不匹配和药物不遵守。目前，遗传和蛋白质建模的进展允许对供体和受体HLA分子之间的相似性和差异进行更详细的比较。这些新技术能够研究表位（分子的子段），而不是整个HLA分子，并确定移植供体和受体之间是否存在匹配的发作。在独立研究中，我们发现表位不匹配和亚临床（未在临床上欣赏，仅通过电子监测检测）不遵守药物不遵守肾脏移植结果。我们的初步数据表明，它们是独立的，协同的，与后期排斥和移植损失相关的相关性。为了准备R34赠款，我们组建了一个在肾脏移植临床试验，药物不遵守（尤其是在移植药物不坚持下）和转化人类免疫学研究方面具有丰富经验的国际多学科团队。该审判将在8个致力于的北美中心进行。 R34赠款的目的是制定并最终确定一项为期5年研究的建议。 5年赠款的目标将是：（1）确定 - 一个前瞻性，多样化的“现实世界”队列 - 表位不匹配和早期亚临床药物对从头供体供体特异性抗体，急性拒绝，谷物功能障碍以及谷物功能障碍和差异的独立和协同影响；（2）定义特定的免疫主导表位是否存在与接受者种族无关；（3）在接受早期亚临床的前瞻性随机对照研究中学习药物不遵守，改善后续依从性的干预是否会减轻早期不遵守性和/或表位不匹配对移植结果的影响。我们的表位不匹配加上亚临床药物不遵守的第一个前瞻性研究。这将是第一个确定不遵守的人（一个亚组如果高风险组延迟排斥和谷物丢失），如果具有乳头状且可能适用于临床使用的多组分干预措施将降低持续的药物不遵守，从而改变早期药物不坚持的影响（或没有表现不匹配或没有表现不匹配）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。