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）：系统性青少年特发性关节炎（SJIA）是一种慢性、经常复发和缓解的儿童风湿病，以发烧、皮疹、关节炎和浆膜炎为特征。虽然病因不明，但SJIA并发症如巨噬细胞激活综合征和淀粉样变性支持先天免疫系统的参与，以及自身抗体或MHC等位基因的缺乏易患疾病。通过转录分析和其他研究，主要来源于单核细胞的促炎细胞因子，包括IL-18、MIF、IL-6和IL-1，与SJIA的发病机制有关。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免疫功能障碍的确切性质尚不清楚。我们在单核细胞中发现了一些新的表型，证实了单核细胞是SJIA的中心效应细胞的观点。单核细胞的扩张和激活在SJIA耀斑中是突出的。在爆发和静止状态下，SJIA单核细胞对凋亡刺激都有抵抗性，无论是内在的还是外在的，可能至少部分是由于Bid切割和表面FasL水平的降低。我们还观察到SJIA单核细胞的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导致SJIA，因为在缓解期和停药期的SJIA受试者中存在一些异常表型。RAPPORT试验提供了一个独特的机会来阐明IL-1在这些表型产生中的作用。这项IL-1抑制剂Rilanocept的随机、安慰剂对照试验将招募100名活性SJIA患者。我们将检测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性水平，我们将评估单核细胞表型与疾病活动性的相关性。第二次分析将为我们在SJIA受试者独立队列中先前研究的结论提供重要检验。对于选定的表型，我们将扩展我们对潜在细胞机制的研究，使用我们收集的SJIA样本对候选机制进行初步评估。当SJIA单核细胞的新特征被定义时，它们将在RAPPORT样本中进行测试，IL-1在这些特征中的作用将通过测试rilonaccept治疗对象的样本来确定。在额外的单变量和多变量分析中，我们将确定特定异常的SJIA单核细胞表型是否预测对利洛那接受治疗的反应。