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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：
9087539
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087539
关键词：
AIDS/HIV problem Address Adoptive Transfer Adult Affect American Antigens Apoptosis Apoptotic Automobile Driving Biopsy CD4 Positive T Lymphocytes Cardiovascular Diseases Cell Count 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 Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukin-17 Intestines Intrinsic factor Kinetics Laboratories Lymphoid Lymphoid Cell Lymphoid Tissue Malignant Neoplasms Mediating Molecular Mus Obesity Pathogenesis Pathologic Pathway interactions Patients Play Population Prevalence Process Production Public Health Publishing Regulation Regulatory Pathway Relative (related person)Role T cell response T-Lymphocyte Tamoxifen Testing Therapeutic Thymic epithelial cell Tissues Transgenic Mice Ulcerative Colitis Up-Regulation Viral hepatitis base commensal microbes cytokine design differential expression disorder control effective therapy human disease in vivo mouse model novel novel therapeutics patient population prevent progenitor promoter response selective expression socioeconomics 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 CD4+ T cell responses against commensal bacteria via major histocompatibility complex class II (MHCII)-dependent interactions. Critically, genetic deletion of MHCII in murine ILC3s results in T cell- dependent intestinal inflammation, and pediatric Crohn's disease patients 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 i both children and adults, in addition to multiple other chronic inflammatory diseases associated with dysregulated immune responses to commensal bacteria.