Immune regulation of intestinal health and disease

肠道健康和疾病的免疫调节

基本信息

批准号：
9893780
负责人：
Gregory F Sonnenberg
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893780
关键词：
AIDS/HIV problem Address Adult Affect American Antigen-Presenting Cells Antigens Apoptosis Automobile Driving Biopsy CD4 Positive T Lymphocytes Cardiovascular Diseases Cell Death Cells Child Childhood Chronic Coculture Techniques Crohn&apos s disease Data Development Diabetes Mellitus Disease Exhibits Gastrointestinal tract structure Genetic Health Histocompatibility Antigens Class II Homeostasis Human Immune Immune response Immunity In Vitro Incidence Induction of Apoptosis Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-17 Interleukin-2 Intestines Intrinsic factor Kinetics Knowledge Laboratories Lymphoid Cell Lymphoid Tissue Malignant Neoplasms Mediating Molecular Mus Nature Neuropilin-1 Obesity Pathogenesis Pathologic Pathway interactions Patients Pediatric Crohn&apos s disease Play Population Prevalence Process Production Public Health Publishing Regulation Regulatory Pathway Role Science Semaphorins Surface T cell response T-Lymphocyte Tamoxifen Testing Therapeutic Thymic epithelial cell Thymus Gland Tissues Transgenic Mice Ulcerative Colitis Viral hepatitis base chronic inflammatory disease commensal bacteria cytokine design differential expression disorder control effective therapy health economics human disease immunoregulation in vivo inflammatory disease of the intestine mouse model neutralizing antibody novel novel therapeutics patient population prevent progenitor promoter public health relevance response selective expression socioeconomics targeted treatment tissue repair translational approach translational study

项目摘要

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a growing public health and socio-economic challenge that affects pediatric and adult populations worldwide. However, the pathogenesis of IBD is poorly understood and therapeutic options are limited and often ineffective. Basic and translational studies suggest that IBD is causally-associated with the development of pro-inflammatory CD4+ T cell responses directed against normally beneficial intestinal commensal bacteria. Therefore interrogating the mechanisms that limit pathologic immune responses to commensal bacteria in the context of health and intestinal inflammation will be critical for the development of novel therapeutics to prevent and treat IBD. Recent studies from this and other laboratories have identified a role for populations of innate lymphoid cells (ILCs) in regulating cytokine-mediated immunity, inflammation and tissue repair in the intestine. In recently published and new preliminary data we have identified that group 3 ILCs (ILC3s) also play a critical role in directly limiting the development of pro- inflammatory commensal bacteria-specific CD4+ T cells via major histocompatibility complex class II (MHCII)- dependent interactions (Hepworth et al. Nature, 2013 and Hepworth et al., Science, 2015). Critically, genetic deletion of MHCII in murine ILC3s results in T cell-dependent intestinal inflammation, and pediatric Crohn's disease patient's exhibit reduced MHCII expression on intestinal ILC3s. These findings provoke the central hypothesis that MHCII+ ILC3s critically regulate pro-inflammatory CD4+ T cell responses to commensal bacteria and are essential to maintain tissue homeostasis in the gastrointestinal tract of humans. We will employ these powerful basic and translational approaches to delineate the pathways by which ILC3s regulate pathologic CD4+ T cell responses to commensal bacteria and intestinal inflammation. Two specific aims of this project will determine (i) the cellular and molecular mechanisms by which MHCII+ ILC3s regulate pathologic commensal bacteria-specific CD4+ T cells, and (ii) what regulates ILC3-intrinsic MHCII expression in the healthy and inflamed intestine of mice and humans. Collectively, these studies will systematically interrogate the role and regulation of ILC3-intrinsic MHCII in basic mouse models, and pioneer translational studies examining these pathways in healthy human and IBD patient populations. These studies will inform ongoing efforts to develop effective therapies targeting ILCs to prevent or treat IBD in both children and adults, in addition to multiple other chronic inflammatory diseases associated with dysregulated immune responses to commensal bacteria.

描述（由申请人提供）：炎症性肠病 (IBD) 是一个日益严重的公共卫生和社会经济挑战，影响着全世界的儿童和成人。然而，人们对 IBD 的发病机制知之甚少，治疗选择有限且常常无效。转化研究表明 IBD 与针对通常有益的肠道共生细菌的促炎性 CD4+ T 细胞反应的发展因此，探究在健康和肠道炎症的背景下限制对共生细菌的病理性免疫反应的机制对于开发预防和治疗的新疗法至关重要。该实验室和其他实验室的最新研究已经确定了先天淋巴细胞 (ILC) 群体在调节肠道细胞因子介导的免疫、炎症和组织修复中的作用。在最近发表的新初步数据中，我们发现了这一点。第 3 组 ILC (ILC3) 还通过主要组织相容性复合物 II 类 (MHCII) 依赖性相互作用，在直接限制促炎共生细菌特异性 CD4+ T 细胞的发育方面发挥着关键作用（Hepworth 等人，Nature，2013 和 Hepworth 等人） al., Science, 2015），重要的是，小鼠 ILC3 中 MHCII 的基因缺失会导致 T 细胞依赖性肠道炎症和小儿克罗恩病。患者肠道 ILC3 上的 MHCII 表达降低，这些发现提出了一个中心假设：MHCII+ ILC3 关键性地调节促炎性 CD4+ T 细胞对共生细菌的反应，对于维持人类胃肠道的组织稳态至关重要。以及描述 ILC3 调节病理性 CD4+ T 细胞对共生细菌和肠道炎症反应的途径的转化方法将确定该项目的两个具体目标。 (i) MHCII+ ILC3 调节病理性共生细菌特异性 CD4+ T 细胞的细胞和分子机制，以及 (ii) 调节小鼠和人类健康和发炎肠道中 ILC3 内在 MHCII 表达的细胞和分子机制。探究 ILC3 内在 MHCII 在基本小鼠模型中的作用和调节，并开创性的转化研究在人类和 IBD 健康患者群体中检查这些途径。为持续努力开发针对ILC的有效疗法提供信息，以预防或治疗儿童和成人的IBD，以及与共生细菌免疫反应失调相关的多种其他慢性炎症性疾病。