IL1 as a Driver of Mucosal Immune Dysregulation in Inflammatory Bowel Disease

IL1 作为炎症性肠病粘膜免疫失调的驱动因素

• 批准号: 10351589
• 负责人: Vanessa Mitsialis
• 金额: $ 16.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-10 至 2027-02-04
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351589
• 关键词: Affect; Biological Response Modifier Therapy; Blood; Cell physiology; Cells; Chronic; Clinical; Colitis; Crohn' s disease; Cytometry; Data; Data Set; Development; Disease; Environmental Risk Factor; Family; Gastroenterology; Gene Proteins; Genetic; Human; Immune; Immunophenotyping; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1; Interleukin-10; Interleukin-12; Intestinal Mucosa; Intestines; Investigation; Life; Mediating; Morbidity - disease rate; Mucositis; Mucous Membrane; Mus; Myelogenous; Pathogenesis; Patients; Peripheral; Phenotype; Play; Population; Production; Proteins; Proteomics; Refractory Disease; Role; Sampling; Severities; Signal Transduction; Stem cell transplant; TNF gene; Technology; Testing; Therapeutic; Tissues; Ulcerative Colitis; Validation; Work; base; cohort; cytokine; disease phenotype; disorder subtype; early onset; gut microbiota; improved; interleukin-10 receptor; macrophage; patient subsets; population based; prospective; protein expression; proteomic signature; receptor; recruit; response; single cell analysis; single-cell RNA sequencing; stem cells; therapeutic target; trafficking; transcriptomics

Project Summary/Abstract Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition affecting the human intestine associated with significant morbidity and limited therapeutic options. Based on the current understanding of IBD pathogenesis, mucosal inflammation seems to arise from a dysregulated crosstalk between intestinal microbes and poorly understood host immune, genetic, and environmental factors. Current biologic therapies available for IBD target specific cytokines (e.g. TNF, IL12/23) or trafficking receptors but a substantial proportion of patients either lose response to, or have disease refractory to, these therapies. There is an urgent need to improve our understanding of IBD pathogenesis to fuel the discovery of additional therapeutic targets. Based on previous investigations, interleukin-1 (IL1) and its associated cytokine family may play a critical role in IBD pathogenesis. IL10 receptor (IL10R)-deficiency, a monogenic form of CD-like IBD leading to colitis and perianal disease within the first year of life, is characterized by enhanced IL1 production in macrophages in both patients and mice. Blockade of IL1 signaling reduces the severity of colitis in IL10R-deficient mice, and several IL10R-deficient patients have been successfully treated with anti-IL1 therapy as a bridge to curative stem cell transplantation. Deep mucosal and peripheral immunophenotyping of a large cohort of IBD and non- IBD subjects using mass cytometry (CyTOF) (Mitsialis et al, Gastroenterology, 2020) has demonstrated that active IBD, especially CD, is characterized by enhanced IL1 expression in specific myeloid populations. Although anti-IL1 therapy is not currently used in the treatment of IBD, this data has led to the hypothesis that there may be subsets of IBD patients with IL1-mediated inflammation, similar to IL10R-deficient patients, whose disease may be amenable to anti-IL1 therapy. This project aims test this hypothesis by specifically interrogating IL1-related transcriptomic and proteomic signatures in IBD. The aims of this project are to (1) define IL1-associated cellular populations in human intestinal mucosa and blood using single cell analyses (CyTOF and scRNA-seq), and (2) determine how these IL1-associated populations differ in IBD, non-IBD, and IL10R-deficient subjects, thereby enabling characterization of IBD phenotypes associated with an enhanced IL1 signature. It is anticipated that IBD patients with an enhanced IL1 signature may share transcriptomic/proteomic findings with IL10R-deficient patients and be defined by a common clinical disease phenotype such as stricturing, fistulizing, or otherwise severe disease. The hope is that the results of this work will guide and set the stage for anti-IL1 therapeutics in IBD.

项目总结/摘要 炎症性肠病（IBD）由克罗恩病（CD）和溃疡性结肠炎（UC）组成，是一种慢性炎症性肠病， 影响人类肠道的炎症性疾病与显著的发病率和有限的 治疗选择根据目前对IBD发病机制的理解，粘膜炎症似乎 由肠道微生物和对宿主免疫，遗传， 和环境因素。目前可用于IBD的生物疗法靶向特异性细胞因子（例如TNF， IL 12/23）或运输受体，但相当大比例的患者对IL 12/23或运输受体失去应答或患有疾病。 对这些疗法无效。我们迫切需要提高对IBD发病机制的认识， 为发现更多的治疗靶点提供了动力。 基于先前的研究，白细胞介素-1（IL-1）及其相关的细胞因子家族可能起关键作用 在IBD发病机制中的作用。IL 10受体（IL 10 R）缺陷，导致结肠炎的CD样IBD的单基因形式， 肛周疾病的特点是在巨噬细胞中IL 1的产生增加， 患者和小鼠。IL 1信号传导的阻断降低了IL 10 R缺陷小鼠结肠炎的严重程度， 一些IL-10受体缺乏的患者已经成功地用抗IL-1治疗作为治愈性的桥梁， 干细胞移植IBD和非IBD患者的大队列的深层粘膜和外周免疫表型 IBD受试者使用质谱细胞术（CyTOF）（Mitsialis et al，Gastroenterology，2020）证明， 活动性IBD，特别是CD，特征在于在特定的骨髓细胞群中增强的IL 1表达。 尽管抗IL-1疗法目前未用于IBD的治疗，但该数据导致了以下假设： 可能存在患有IL 1介导的炎症的IBD患者亚群，类似于IL 10 R缺陷患者， 其疾病可能适合抗IL 1治疗。 本项目旨在通过特异性地询问IL-1相关的转录组学和蛋白质组学来验证这一假设。 在IBD签名。本项目的目的是：（1）确定人类IL-1相关细胞群 使用单细胞分析（CyTOF和scRNA-seq）检测肠粘膜和血液，以及（2）确定这些 IL 1相关人群在IBD、非IBD和IL 10 R缺陷受试者中不同，从而使得 与增强的IL 1标签相关的IBD表型的表征。预计IBD IL 1信号增强的患者可能与IL 10 R缺陷的患者具有相同的转录组学/蛋白质组学结果。 患者，并由常见的临床疾病表型定义，例如狭窄、瘘管形成或其他 严重的疾病。希望这项工作的结果将指导并为抗IL-1治疗奠定基础， IBD。