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发性出血性心绞痛患者群体的研究来全面阐述上述机制。这项申请提出了一系列研究，将利用独特的机会使用来自Treat(积极治疗试验)临床试验的样本。治疗将测试ETN、强的松龙和MTX的积极早期治疗是否会比传统治疗(单独使用MTX)更频繁地在多发性JIA患者中导致非活动期疾病(ID)状态。使用适当设计和统计动力的方法，该项目将确定治疗应答者和无应答者的免疫通路特征，并确定不同免疫细胞群体之间的相互作用的致病相关性。这一知识还应导致通过调整治疗方案来抢救无反应者的战略。这些研究还将确定免疫耐受/抑制机制是否在没有保持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效果的有用生物标志物。该项目的中心假设是，甲氨蝶呤(MTX)单独或与依那西普(ETN)和强的松龙联合使用的有效治疗通过影响多个相互依赖的免疫途径，包括T细胞调节(Treg)、T效应的谱系承诺(Th-1-3，17)和APC功能，从而导致多关节幼年特发性关节炎(PolyJIA)的非活动期疾病(ID)。正是多个途径的相互作用，而不是单一的机制，导致了免疫下调和临床改善。具体目标一：确定经治疗改变的Treg机制；具体目标二：确定治疗诱导的Tef的谱系承诺(TH-1-3，17)的功能变化；特定目标III：确定治疗诱导的APC功能变化；特定目标IV：确定T-APC串扰在功能上与免疫耐受相关的机制；特定目标五：确定疾病活动和治疗反应的生物标志物；特定目标VI：评估先前目标的研究结果与临床结果的相关性。公共卫生相关性：项目叙述(最多3句话)这里建议的工作为治疗临床试验提供了一个基本的机械-翻译出口，将分子免疫学机制与临床结果联系起来，并有望通过详细确定最新疗法对免疫系统各个组成部分的影响，为儿童风湿学领域的重大进步做出贡献。该项目有可能提供关于人类免疫耐受的免疫学以及JIA和/或治疗反应的生物标记物的有价值的信息。如果某些生物标记物不能检测到这一设置中的差异，那么它们在临床设置中更不可能有帮助，因此这些研究将为了解哪些测试是和不值得在未来评估其在临床设置中的表现奠定框架。

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.