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聚JIA患者种群的研究，可以全面解决上述机制。该应用程序提出了一系列研究，该研究将利用独特的机会使用该临床试验（侵略性疗法试验）中的样本。治疗将测试与传统疗法（单独使用MTX）更频繁地使用ETN，泼尼松龙和MTX对多JIA患者的非活性疾病（ID）状态的侵略性早期治疗。该项目使用适当设计和统计上动力的方法，将确定治疗响应者和非反应者的免疫途径特征，并确定各种免疫细胞种群之间交叉言论的致病性相关性。这些知识还应通过调整治疗方案来实现营救非反应者的策略。这些研究还将确定免疫耐受性/抑制的机制是否在不维持ID的患者中效率较低，或者在从未达到ID的患者中受到损害。通过将临床干预与机械研究联系起来，这些研究还将确定疾病活动和治疗功效的有用的生物标志物。该项目的中心假设是，单独或与依那耐（ETN）和泼尼松酮结合使用甲氨蝶呤（MTX）的有效疗法，在多关节幼年性特发性关节炎（poly JIA）中诱导​​无效疾病（ID），通过影响多个互依赖的免疫途径（包括the），包括17个疾病，包括th- the threake（poly jiA），包括th-17 fiors threake（Treg），Threage（Treg），linea效应（Treg），Treg（Treg），Treg），TREG效应（Treg）。 （TEFF）和APC功能。这是多种途径之间的相互作用，而不是单个机制，这导致了免疫学下调和临床改善。特定目的I：确定通过治疗修改的Treg机制；特定目的II：确定TEFF的谱系承诺的治疗诱导的功能变化（TH-1-3，17）；特定目标III：确定治疗诱导的APC功能变化；特定目的IV：确定T-APC串扰的机制在功能上与免疫耐受性相关；特定目的V：确定疾病活动和治疗反应的生物标志物；特定目标VI：评估以前目标与临床结果的发现的相关性。公共卫生相关性：项目叙事（3句话最大）此处提出的工作为治疗临床试验提供了基本的机械性转换出口，将分子免疫学机制与临床结果联系起来，并预计有助于通过详细识别各种治疗效果的儿科风湿病学领域，在各种疗法的效果中鉴定出各种疗法的影响。该项目有潜力提供有关人类免疫耐受性和JIA和/或治疗反应的生物标志物免疫学的有价值信息。如果某些生物标志物无法检测到这种环境中的差异，那么它们在临床环境中的可能性较小，因此这些研究将为理解哪些测试是并且将来不值得评估的框架为其在临床环境中的表现而言不值得评估。