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）：系统性幼年特发性关节炎（SJIA）是一种慢性、经常复发和缓解的儿童期风湿病，其特征是发烧、皮疹、关节炎和浆膜炎。尽管病因尚不清楚，但巨噬细胞活化综合征和淀粉样变性等 SJIA 并发症支持先天免疫系统的参与，自身抗体或 MHC 等位基因的缺乏也导致疾病。转录分析和其他研究表明，主要源自单核细胞的促炎细胞因子，包括 IL-18、MIF、IL-6 和 IL-1，与 SJIA 发病机制有关。不过，IL-1 和 IL-6 的关键作用也得到了对其抑制作用的显着临床反应的支持，至少在部分患者中是如此。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几种新的表型，证实了单核细胞是 SJIA 中的中心效应细胞的观点。单核细胞的扩增和激活在 SJIA 耀斑中非常突出。在爆发和静止状态下，SJIA 单核细胞对内在和外在的细胞凋亡刺激都有抵抗力，这可能至少部分归因于 Bid 裂解和表面 FasL 水平的降低。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，因为在缓解、停止用药的 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 在这些表型生成中的作用。这项 IL-1 抑制剂 Rilanocept 的随机、安慰剂对照试验将招募 100 名患有活动性 SJIA 的受试者。我们将在 IL-1 阻断前后检测从 SJIA 受试者分离的单核细胞，以评估 IL-1 在每种表型中的作用。此外，利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独立的 SJIA 受试者队列中进行的研究得出的结论进行重要检验。对于选定的表型，我们将使用我们收集的 SJIA 样本来扩展对潜在细胞机制的研究，以对候选机制进行初步评估。当确定 SJIA 单核细胞的新特征时，将在 RAPPORT 样本中对其进行测试，并且将通过测试来自 Rilonacept 治疗受试者的样本来确定 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 单核细胞表型是否可以预测对 Rilonacept 治疗的反应。 公共卫生相关性（由申请人提供）：系统性特发性幼年关节炎 (SJIA) 是一种慢性儿童疾病，会导致关节炎、发烧、皮疹和其他类型的炎症（例如心脏和肺部周围）。目前尚不清楚导致这种疾病的原因，但一些患者对抑制 IL-1（人体产生的炎症介质）的药物有反应。结合 IL-1 抑制剂 Rilanocept 的试验，我们建议研究 IL-1 如何影响特定的免疫细胞类型（单核细胞），单核细胞似乎是 SJIA 病理学中的关键细胞。我们还希望确定疾病期间单核细胞的变化，以预测对 Rilanocept 的反应。