Mechanisms of Immune Modulation in JIA

幼年特发性关节炎的免疫调节机制

• 批准号: 7937821
• 负责人: Salvatore Albani
• 金额: $ 41.03万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937821
• 关键词: Address; Affect; Area; Art Therapy; Biological Markers; Cells; Characteristics; Childhood; Chronic Childhood Arthritis; Clinical; Clinical Treatment; Clinical Trials; Complement; Disease; Down-Regulation; Early treatment; Etanercept; Future; Human; Immune; Immune Tolerance; Immune system; Immunology; Intervention; Knowledge; Lead; Link; Measurement; Methotrexate; Molecular; Molecular Target; Outcome; Pathway interactions; Patients; Performance; Population; Reaction Time; Regimen; Regulatory T-Lymphocyte; Relative (related person); Rheumatology; Sampling; Series; T cell regulation; T-Lymphocyte; Testing; Therapeutic; Therapy Clinical Trials; Time; Treatment Efficacy; Work; aggressive therapy; anergy; base; conventional therapy; cytokine; design; effective therapy; immunoregulation; patient population; prednisolone; public health relevance; response; treatment response

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.

描述（由申请人提供）： 目前尚无基于统一选择的多发性幼年特发性关节炎患者群体的研究来全面解决上述机制。该申请提出了一系列研究，这些研究将利用使用 TREAT（积极治疗试验）临​​床试验样本的独特机会。 TREAT 将测试使用 ETN、泼尼松龙和 MTX 进行积极的早期治疗是否会比传统治疗（单独使用 MTX）更频繁地诱发多聚 JIA 患者的非活动性疾病 (ID) 状态。该项目将使用适当设计和统计支持的方法，识别治疗反应者和非反应者的免疫途径特征，并确定不同免疫细胞群之间串扰的致病相关性。这些知识还应该导致通过调整治疗方案来拯救无反应者的策略。这些研究还将确定免疫耐受/抑制机制是否在未维持 ID 的患者中变得效率较低，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，单独使用甲氨蝶呤 (MTX) 或与依那西普 (ETN) 和泼尼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 效应器的谱系定型 (Th-1-3, 17)，诱导多关节幼年特发性关节炎 (poly JIA) 的非活动性疾病 (ID) (Teff) 和 APC 功能。导致免疫下调和临床改善的是多种途径之间的相互作用，而不是单一机制。具体目标 I：确定治疗改变的 Treg 机制；具体目标 II：确定治疗引起的 Teff 谱系定型 (TH-1-3, 17) 功能变化；具体目标 III：确定治疗引起的 APC 功能变化；具体目标 IV：确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：评估先前目标的发现与临床结果的相关性。公共健康相关性：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转化途径，将分子免疫机制与临床结果联系起来，并预计通过详细确定最先进的治疗对免疫系统各个组成部分的影响，为儿科风湿病领域的重大进步做出贡献。该项目有可能提供有关人类免疫耐受的免疫学以及幼年特发性关节炎和/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无法检测到这种情况下的差异，那么它们在临床环境中就更不可能有帮助，因此这些研究将为了解哪些测试值得和不值得在未来评估其在临床环境中的表现奠定框架。