A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study

IL-1 在 SJIA 单核细胞表型中的作用：一项 RAPPORT 辅助研究

• 批准号: 8088935
• 负责人: Elizabeth D Mellins
• 金额: $ 32.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-22 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088935
• 关键词: role; IL; SJIA; monocyte; phenotypes

DESCRIPTION (provided by applicant): Systemic juvenile idiopathic arthritis (SJIA) is a chronic, often relapsing and remitting, rheumatic condition of childhood, characterized by fever, rash, arthritis and serositis. Although the etiology is unknown, SJIA complications such as macrophage activation syndrome and amyloidosis support involvement of the innate immune system, as do the paucity of autoantibodies or MHC alleles that predispose to disease. Pro-inflammatory cytokines that are principally monocyte-derived, including IL-18, MIF, IL-6 and IL-1, are implicated in SJIA pathogenesis by transcriptional analysis and other studies. Key roles for IL-1 and IL-6 also are supported by striking clinical responses to their inhibition, at least in subsets of patients, although. The exact nature of the immune dysfunction in SJIA is unknown, however. We have found several novel phenotypes in monocytes that corroborate the idea that monocytes are a central effector cell in SJIA. Monocyte expansion and activation are prominent at SJIA flare. At both flare and quiescence, SJIA monocytes are resistant to apoptotic stimuli, both intrinsic and extrinsic, likely due at least in part to reduced levels of Bid cleavage and surface FasL, respectively. We also observe reduced interferon signaling in SJIA monocytes and increased LPS-stimulated IL-1¿ secretion. Our findings suggest that aberrant monocyte function may predispose to SJIA, because some abnormal phenotypes are present in SJIA subjects in remission, off medication. The RAPPORT trial offers a unique opportunity to elucidate the role of IL-1 in the generation of these phenotypes. This randomized, placebo-controlled trial of the IL-1 inhibitor Rilanocept will enroll 100 subjects with active SJIA. We will assay monocytes isolated from SJIA subjects before and after IL-1 blockade to assess the role of IL-1 in each phenotype. Also, using clinical information to define level of disease activity, we will assess the correlation of monocyte phenotype with disease activity. This second analysis will provide an important test of conclusions from our prior studies in an independent cohort of SJIA subjects. For selected phenotypes, we will extend our investigation of the underlying cellular mechanisms, using SJIA samples from our collection for initial evaluation of candidate mechanisms. When new features of SJIA monocytes are defined, they will be tested in the RAPPORT samples, and the role of IL-1 in these features will be established by testing samples from Rilonacept-treated subjects. In additional univariate and multivariate analyses, we will determine whether particular abnormal SJIA monocyte phenotype(s) predicts response to Rilonacept treatment. PUBLIC HEALTH RELEVANCE (provided by applicant): Systemic idiopathic juvenile arthritis (SJIA) is a chronic childhood disease that causes arthritis, fever, rash and other kinds of inflammation (e.g. around the heart and lungs). It is unknown what causes this disease, but some patients respond to medication that inhibits IL-1, an inflammatory mediator made by the body. In conjunction with a trial of the IL-1 inhibitor Rilanocept, we propose to investigate how IL-1 affects a particular immune cell type, the monocyte, which appears to be a key cell in SJIA pathology. We also hope to identify changes in monocytes during disease that predict response to Rilanocept.

描述（由申请人提供）：全身性幼年特发性关节炎（SJIA）是一种慢性、经常复发和缓解的儿童风湿性疾病，以发热、皮疹、关节炎和浆膜炎为特征。虽然病因不明，但SJIA并发症如巨噬细胞活化综合征和淀粉样变性支持先天免疫系统的参与，以及缺乏易患疾病的自身抗体或MHC等位基因。通过转录分析和其他研究，主要是单核细胞衍生的促炎细胞因子，包括IL-18、MIF、IL-6和IL-1，与SJIA发病机制有关。尽管如此，IL-1和IL-6的关键作用也得到了对其抑制的显著临床反应的支持，至少在患者亚群中是如此。然而，SJIA中免疫功能障碍的确切性质尚不清楚。我们已经发现了几个新的单核细胞表型，证实了单核细胞是一个中央效应细胞在SJIA的想法。单核细胞扩增和活化在SJIA发作时显著。在爆发期和静止期，SJIA单核细胞对内源性和外源性凋亡刺激具有抗性，这可能至少部分是由于Bid裂解和表面FasL水平降低。我们还观察到SJIA单核细胞中干扰素信号传导减少，LPS刺激的IL-1？分泌增加。我们的研究结果表明，异常的单核细胞功能可能易患SJIA，因为一些异常的表型存在于SJIA受试者缓解，停药。RAPPORT试验为阐明IL-1在这些表型产生中的作用提供了独特的机会。这项随机、安慰剂对照的IL-1抑制剂利凡诺塞试验将招募100名活动性SJIA患者。我们将分析IL-1阻断前后从SJIA受试者中分离的单核细胞，以评估IL-1在每种表型中的作用。此外，使用临床信息来定义疾病活动水平，我们将评估单核细胞表型与疾病活动的相关性。第二次分析将对我们之前在一个独立的SJIA受试者队列中进行的研究的结论进行重要检验。对于选定的表型，我们将扩大我们的调查的基础细胞机制，使用SJIA样本从我们收集的候选机制的初步评估。当定义SJIA单核细胞的新特征时，将在RAPPORT样本中对其进行检测，并通过检测接受阿托纳西治疗的受试者样本确定IL-1在这些特征中的作用。在额外的单变量和多变量分析中，我们将确定特定的异常SJIA单核细胞表型是否预测对阿托纳西普治疗的反应。 公共卫生相关性（由申请人提供）：全身性特发性幼年关节炎（SJIA）是一种慢性儿童疾病，可引起关节炎、发热、皮疹和其他类型的炎症（例如，心脏和肺部周围）。目前尚不清楚是什么原因导致这种疾病，但一些患者对抑制IL-1的药物有反应，IL-1是一种由身体产生的炎症介质。结合IL-1抑制剂的试验，我们建议研究IL-1如何影响一种特定的免疫细胞类型，单核细胞，这似乎是一个关键的细胞在SJIA病理。我们还希望确定疾病期间单核细胞的变化，预测对阿托诺塞的反应。