Mechanisms of Immune Modulation in JIA

描述（由申请人提供）： 目前还没有基于统一选择的多聚JIA患者人群的研究全面阐述上述机制。本申请提出了一系列研究，这些研究将利用TREAT（积极治疗试验）临床试验的独特机会。TREAT将测试ETN、泼尼松龙和MTX的积极早期治疗是否会比常规治疗（单独MTX）更频繁地诱导poly-JIA患者的非活动性疾病（ID）状态。使用适当设计和统计学功效的方法，该项目将识别治疗应答者和非应答者的免疫途径特征，并识别各种免疫细胞群体之间串扰的致病相关性。这方面的知识也将导致通过调整治疗方案来挽救无应答者的策略。这些研究还将确定免疫耐受/抑制机制是否在不维持ID的患者中变得不那么有效，或者在从未实现ID的患者中受损。通过将临床干预与机制研究联系起来，这些研究还将确定疾病活动和治疗疗效的有用生物标志物。该项目的中心假设是甲氨蝶呤（MTX）单独或与依那西普（ETN）和泼尼松龙组合的有效疗法通过影响多个相互依赖的免疫途径（包括T细胞调节（Treg）、T效应子（Teff）的谱系定型（Th-1-3，17）和APC功能）在多关节幼年特发性关节炎（poly JIA）中诱导非活动性疾病（ID）。这是多个途径之间的相互作用，而不是单一机制，导致免疫下调和临床改善。具体目标一：确定治疗改变的Treg机制;具体目标II：确定治疗诱导的谱系定型功能变化（TH-1-3，17）;具体目标III：鉴定治疗诱导的APC功能变化;具体目标IV：鉴定与免疫耐受功能相关的T-APC串扰机制;具体目标V：确定疾病活动和治疗反应的生物标志物;具体目标VI：评估先前目标的结果与临床结局的相关性。公共卫生相关性：项目叙述（最多3句话）这里提出的工作为TREAT临床试验提供了一个基本的机制-翻译出口，将分子免疫学机制与临床结果联系起来，并通过详细确定最先进疗法对免疫系统各组成部分的影响，预计将有助于儿科风湿病学领域的重大进展。该项目有可能提供有关人类免疫耐受的免疫学和JIA和/或治疗反应的生物标志物的有价值的信息。如果某些生物标志物在这种情况下无法检测到差异，那么它们在临床环境中更不可能有帮助，因此这些研究将为理解哪些测试值得和不值得在未来评估其在临床环境中的性能奠定框架。

DESCRIPTION (provided by applicant): There are currently no studies based on uniformly selected populations of patients with poly JIA that address comprehensively the mechanisms outlined above. This application proposes a series of studies which will capitalize on the unique opportunity to use samples from the TREAT (The Trial of Aggressive Therapy) clinical trial. TREAT will test whether aggressive early therapy with ETN, prednisolone and MTX will induce an inactive disease (ID) state in patients with poly-JIA more frequently than conventional therapy (MTX alone). Using an appropriately designed and statistically powered approach, this project will identify immune pathways characteristic of treatment responders and non-responders and identify the pathogenic relevance of the cross- talk between various populations of immune cells. This knowledge should also lead to strategies for the rescue of non-responders by adjustments of the therapeutic regimens. These studies will also identify whether mechanisms of immune tolerance/suppression become less efficient in patients who do not maintain ID, or are impaired in patients who never achieve ID. By linking clinical intervention with mechanistic studies, these studies will also identify useful biomarkers of disease activity and treatment efficacy. The central hypothesis for this project is that effective therapies with methotrexate (MTX) alone or in combination with Etanercept (ETN) and prednisolone induce inactive disease (ID) in polyarticular juvenile idiopathic arthritis (poly JIA) by affecting multiple interdependent immune pathways, including T cell regulation (Treg), lineage commitment (Th-1-3, 17) for T effector (Teff) and APC function. It is the interaction among multiple pathways, rather than a single mechanism, which leads to immunological down-regulation and clinical improvement. Specific Aim I: To identify Treg mechanisms which are modified by the treatment; Specific Aim II: To identify treatment-induced functional changes in lineage commitment (TH-1-3, 17) for Teff; Specific Aim III: To identify treatment-induced functional changes in APC; Specific Aim IV: To identify mechanisms of T-APC cross-talk functionally relevant to immune tolerance; Specific Aim V: To identify biomarkers of disease activity and treatment response; Specific Aim VI: To assess the correlation of the findings from the previous aims with clinical outcomes. PUBLIC HEALTH RELEVANCE: Project Narrative (3 sentences Max) The work proposed here provides a fundamental mechanistic-translational outlet to the TREAT clinical trial, connecting molecular immunological mechanisms with clinical outcomes, and is anticipated to contribute to significant advancement in the area of pediatric rheumatology by identifying in detail the effects of state of art therapy on various components of the immune system. This project has the potential to provide valuable information regarding the immunology of human immune tolerance and biomarkers of JIA and/or treatment response. If certain biomarkers are unable to detect differences in this setting then they are even less likely to be helpful in the clinical setting, thus these studies will lay the framework for understanding which tests are and are not worthwhile evaluating in the future for their performance in clinical settings.