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（应用程序提供）：全身少年特发性关节炎（SJIA）是一种慢性，经常复发和恢复，儿童风湿病，以发烧，皮疹，关节炎，关节炎和血清炎为特征。易于疾病的自身抗体或MHC等位基因。通过转录分析和其他研究，在SJIA发病机理中实施了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。 IL-1和IL-6的关键作用也得到了至少在患者亚群中对其抑制作用的惊人临床反应的支持。但是，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型表型，这些表型证实了单核细胞是SJIA中心效应细胞的观念。在SJIA Flare中，单核细胞的扩展和激活是突出的。在耀斑和静止状态下，SJIA单核细胞对固有和外在的凋亡刺激具有抗性，可能至少部分归因于BID裂解水平和表面FASL的水平。我们还观察到SJIA单核细胞中的干扰素信号传导降低，并增加了LPS刺激的IL-1。分泌。我们的发现表明，异常的单核细胞功能可能会易于SJIA，因为SJIA受试者中存在一些异常表型，以缓解药物。 Rapport试验提供了一个独特的机会，可以阐明IL-1在这些表型产生中的作用。 IL-1抑制剂rilanocept的这项随机，安慰剂对照试验将招募100名活跃SJIA受试者。我们将断言IL-1阻滞前后从SJIA受试者中分离出的单核细胞，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性的相关性。第二次分析将为我们在独立的SJIA受试者队列中从我们先前的研究中得出的结论提供重要的测试。对于选定的表型，我们将使用收集的SJIA样品来扩展对潜在细胞机制的研究，以初步评估候选机制。当定义了SJIA单核细胞的新特征时，将在融洽的样本中测试它们，并且通过测试来自Rilonacet处理的受试者的样品来确定IL-1在这些特征中的作用。在其他单变量和多元分析中，我们将确定特定的异常SJIA单核细胞表型是否预测对Rilonacet治疗的反应。 公共卫生相关性（通过应用程序提供）：系统性特发性少年关节炎（SJIA）是一种慢性儿童疾病，会引起关节炎，发烧，皮疹和其他类型的感染（例如，心脏和肺部周围）。尚不清楚导致这种疾病的原因是什么，但是有些患者对抑制人体炎症介质IL-1的药物反应。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，该单核细胞似乎是SJIA病理学中的关键细胞。我们还希望在疾病期间鉴定单核细胞的变化，以预测对Rilanocept的反应。