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: 8325175
• 负责人: Elizabeth D Mellins
• 金额: $ 31.1万
• 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/8325175
• 关键词: Abnormal Monocyte; Acute; Affect; Aftercare; Alleles; Amyloidosis; Ancillary Study; Apoptosis; Apoptotic; Arthritis; Autoantibodies; Autoimmune Diseases; Biological Assay; Blood; CD14 gene; Calcium-Binding Proteins; Cell Lineage; Cell Separation; Cells; Child; Childhood; Chronic; Chronic Childhood Arthritis; Clinical; Clinical Trials; Collection; Disease; Disease remission; Effector Cell; Employee Strikes; Enrollment; Etiology; Evaluation; Exanthema; FCGR3B gene; Fever; Flare; Gene Expression Profile; Generations; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Heart; Hepatosplenomegaly; Immune; Immune System Diseases; Immune system; Immunologics; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Interleukin-1; Interleukin-18; Interleukin-6; Investigation; Lung; Macrophage Activation; Major Histocompatibility Complex; Mind; Multivariate Analysis; Nature; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Play; Production; RNA; Relapse; Relapsing Fever; Resistance; Role; S100A12 gene; S100A8 gene; S100A9 gene; Sampling; Serositis; Serum; Signal Transduction; Specimen; Stimulus; Surface; Syndrome; Synovial Fluid; TNF gene; Testing; Therapeutic; Up-Regulation; Visit; Whole Blood; arm; cell type; cohort; cytokine; inhibitor/antagonist; macrophage; monocyte; novel; public health relevance; randomized placebo controlled trial; receptor; response; sample collection; thrombocytosis

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(申请人提供)：系统性幼年特发性关节炎(SJIA)是一种慢性的，经常复发和缓解的儿童风湿性疾病，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，以及缺乏自身抗体或MHC等易患疾病的基因，都支持先天免疫系统的参与。转录分析和其他研究表明，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-1，参与了SJIA的发病机制。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，至少在部分患者中是这样。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耀斑中非常显著。SJIA单核细胞在活跃和静止状态下都能抵抗内源性和外源性的凋亡刺激，这可能至少部分是由于Bid裂解和表面FasL水平分别降低所致。我们还观察到SJIA单核细胞中干扰素信号的减少和内毒素刺激的IL-1分泌增加。我们的发现提示单核细胞功能异常可能是SJIA的易感因素，因为SJIA患者在缓解期和停药时存在一些异常的表型。Rapport试验提供了一个独特的机会来阐明IL-1在这些表型的产生中的作用。这项IL-1抑制剂Rilanocept的随机、安慰剂对照试验将招募100名SJIA患者。我们将对SJIA患者在IL-1阻断前后分离的单核细胞进行检测，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。第二项分析将在一组独立的SJIA受试者中对我们先前研究得出的结论进行重要检验。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样本来初步评估候选机制。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，而IL-1在这些特征中的作用将通过测试利洛那贝特治疗的受试者的样本来确定。在另外的单变量和多变量分析中，我们将确定特定的SJIA单核细胞表型异常(S)是否预测利洛那塞治疗的疗效。 公共卫生相关性(由申请人提供)：系统性特发性幼年性关节炎(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(如心脏和肺部周围)。目前尚不清楚是什么原因导致了这种疾病，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Rilanocept的试验，我们建议调查IL-1如何影响一种特殊的免疫细胞类型，即单核细胞，它似乎是SJIA病理中的关键细胞。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。