The Reprogramming of Regulatory T cells to a Th17 Phenotype in Systemic Juvenile Idiopathic Arthritis

系统性幼年特发性关节炎中调节性 T 细胞重编程为 Th17 表型

• 批准号: 10374102
• 负责人: Lauren A Henderson
• 金额: $ 16.8万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374102
• 关键词: Acute; Advisory Committees; Affect; Anti-Cytokine Therapy; Arthritis; Bioinformatics; Biological Assay; Biology; Boston; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Chronic; Cytometry; DNA Methylation; Data; Defect; Development; Disease; Effector Cell; Ensure; Environment; Equilibrium; Evolution; Exanthema; Exhibits; FOXP3 gene; Fever; Fostering; Foundations; Frequencies; Functional disorder; Funding; Gene Expression Profile; Generations; Goals; Human; Immune; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-1; Interleukin-1 beta; Interleukin-17; Interleukin-6; Investigation; Joints; Mediating; Mediator of activation protein; Mentors; Methods; Modeling; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Onset of illness; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Predisposing Factor; Production; Refractory; Regulatory T-Lymphocyte; Research; Research Personnel; Research Training; Rheumatology; Role; Sampling; Secure; Site; Suggestion; Symptoms; Synovitis; Techniques; Testing; Time; Training; Translational Research; Work; autoinflammatory; base; biobank; career; collaborative environment; cytokine; demethylation; effective therapy; functional outcomes; in vivo; innovative technologies; inter-institutional; large datasets; methylation pattern; novel; novel strategies; operation; patient subsets; prevent; ranpirnase; skills; success; systemic inflammatory response; systemic juvenile idiopathic arthritis; targeted agent; transcriptome sequencing; transcriptomics; translational scientist; treatment strategy; trend

Project Summary/Abstract The disease course of systemic onset juvenile idiopathic arthritis (sJIA) follows a peculiar pattern compared to other forms of inflammatory arthritis observed in children. The initial phase of the disease is heralded by high fevers, rash, and systemic inflammation, and only a subset of patients develops chronic arthritis. It is well known that IL-1β and IL-6 are key mediators of the systemic symptoms in early sJIA. Our ultimate goals are to better understand the factors that predispose some children to develop chronic arthritis in sJIA so that we can identify effective treatments and strategies to prevent arthritis in this condition altogether. This proposal outlines a research and training plan with a focus on regulatory T cell dysfunction as a mediator of arthritis in sJIA. The investigator conducted preliminary studies that showed abnormalities in Treg cells from patients with acute sJIA, including markedly increased IL-17 production and decreased frequencies of peripherally-induced Treg cells. Based on these findings and the known permissive effects IL-1β and IL-6 have on Th17 polarization, we hypothesize that the inflammatory cytokine environment in early sJIA transforms Treg cells into Th17-like-effector cells and blocks peripherally-induced Treg differentiation. The result is a Th17/Treg imbalance then drives chronic arthritis in sJIA. The proposed Specific Aims will test this hypothesis with human biosamples. In Aim 1, Treg stability and phenotype in sJIA will be determined through the use of mass cytometry, transcriptomics, and DNA methylations studies. Aim 2 evaluates the effects of IL-1β and IL-6 on Treg suppressive capacity and peripherally-induced Treg generation from naïve CD4+ T cells. Using multidimensional immunoprofiling made possible by innovative technologies and functional assays, this project will allow the candidate to develop important skills that will provide the foundation for an independent research career. In the short term, the candidate’s goals are to develop a deeper understanding of Treg- mediated tolerance, leverage cutting-edge techniques such as mass cytometry and RNA sequencing to study patient samples, and master bioinformatic approaches to analyze large data sets. A team of mentors, advisors, and collaborators with the requisite expertise has been assembled to ensure success and allow the applicant to meet the ultimate objective of independence as a translational investigator in the field of pediatric rheumatology.

项目总结/摘要 全身性发作的幼年特发性关节炎（sJIA）的病程遵循一种特殊的模式， 在儿童中观察到的其他形式的炎性关节炎。这种疾病的初始阶段是由高 发烧、皮疹和全身炎症，只有一部分患者会发展为慢性关节炎。公 已知IL-1β和IL-6是sJIA早期全身症状的关键介质。我们的最终目标是 更好地了解sJIA中一些儿童易患慢性关节炎的因素，以便我们能够 确定有效的治疗方法和策略，以防止关节炎在这种情况下完全。 该提案概述了一项研究和培训计划，重点是调节性T细胞功能障碍作为调解人 关节炎的症状。研究人员进行了初步研究，显示Treg细胞的异常， 急性sJIA患者，包括IL-17产生显著增加和 外周诱导的Treg细胞。基于这些发现和已知的IL-1β和IL-6具有的容许效应， 在Th 17极化上，我们假设早期sJIA中的炎性细胞因子环境转化Treg 细胞转化为Th 17样效应细胞并阻断外周诱导的Treg分化。结果是Th 17/Treg 不平衡，然后驱动sJIA慢性关节炎。拟议的具体目标将用人类来检验这一假设。 生物样本在目标1中，将通过使用质量分析来确定sJIA中的Treg稳定性和表型。 细胞计数、转录组学和DNA甲基化研究。目的2评价IL-1β和IL-6对人肝癌细胞增殖的影响。 Treg抑制能力和来自幼稚CD 4 + T细胞的外周诱导Treg产生。 利用创新技术和功能测定所带来的多维免疫分析， 项目将允许候选人发展重要的技能，这将为独立的基础 研究生涯。在短期内，候选人的目标是更深入地了解Treg- 介导的耐受性，利用尖端技术，如大规模细胞计数和RNA测序研究 患者样本，以及分析大型数据集的主要生物信息学方法。一群导师，顾问， 和合作者与所需的专业知识已经组装，以确保成功，并允许申请人 满足作为儿科领域翻译研究者的独立性的最终目标 风湿病学

项目成果

MIS-C: early lessons from immune profiling.

• DOI: 10.1038/s41584-020-00566-y
• 发表时间: 2021-03
• 期刊: Nature reviews. Rheumatology
• 作者: Henderson LA;Yeung RSM
• 通讯作者: Yeung RSM

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2.

• DOI: 10.1002/art.41616
• 发表时间: 2021-04
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Henderson LA;Canna SW;Friedman KG;Gorelik M;Lapidus SK;Bassiri H;Behrens EM;Ferris A;Kernan KF;Schulert GS;Seo P;Son MBF;Tremoulet AH;Yeung RSM;Mudano AS;Turner AS;Karp DR;Mehta JJ
• 通讯作者: Mehta JJ