Regulation of host-commensal relationships in human health and disease

人类健康和疾病中宿主共生关系的调节

基本信息

批准号：
8550839
负责人：
Gregory F Sonnenberg
金额：
$ 38.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550839
关键词：
Address Affect Alcaligenes Antibiotics Antibodies Autoimmune Process Biological Assay Biological Models CD4 Positive T Lymphocytes Cells Chronic Coculture Techniques Colorectal Complex Containment Data Defect Development Disease Economic Burden Epidemiologic Studies Epidemiology Exhibits Future Genes Genetic Goals Gut associated lymphoid tissue Health Histocompatibility Antigens Class II Homeostasis Human Immune Immune response Immune system Immunocompetent Immunoglobulin G Immunologic Tests Immunologics In Vitro Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukins Intestines Link Lymphocyte Lymphoid Lymphoid Cell Maintenance Mammals Mediating Mus Pathogenesis Pathway interactions Patients Peptides Peripheral Population Process Production Public Health Rag1 Mouse Regulation Regulatory T-Lymphocyte Risk Role Sampling Serum Severities Severity of illness Source Symptoms Testing Therapeutic Tissues antimicrobial base commensal microbes cytokine genetic association genome-wide health economics in vivo interleukin-22 intestinal homeostasis microorganism mouse model novel peripheral blood prevent response translational approach translational study

项目摘要

DESCRIPTION (provided by applicant): The human immune system is critical to protect against infection with pathogenic microorganisms. However, inappropriate immune responses against our own tissues or non-harmful environmental triggers such as beneficial commensal bacteria that surround us can promote autoimmune or chronic inflammatory diseases. Indeed, emerging studies in patients and murine model systems indicate that abnormal host-commensal relationships are either associated with or causally linked to numerous chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Genetic association and epidemiologic studies suggest that IBD is associated with dysregulated innate and adaptive immune responses that promote dysregulated host- commensal interactions and commensal bacteria-driven chronic intestinal inflammation. Recent studies have highlighted a role for innate lymphoid cells (ILCs) and their effector cytokine IL-22 in regulating intestinal inflammation. In new preliminary studies, I identified that ILCs are critical for maintenance of selective host- commensal relationships by anatomically-restricting a defined subset of commensal bacteria to the gut associated lymphoid tissues (GALT) of healthy mammals. This selective regulation could occur via two mechanisms; first, an innate pathway of IL-22 cytokine production limited peripheral dissemination of GALT- resident commensal bacteria to prevent systemic inflammation. Second, ILCs directly regulated adaptive immune responses and maintained normal host immune responses to GALT-resident commensal bacteria to prevent intestinal inflammation. Finally, I also observed the presence of ILCs in intestinal samples from healthy human donors, and dysregulated host-commensal relationships to the same defined subset of GALT- resident commensal bacteria in IBD patients. I will employ these powerful basic and translational approaches to delineate the pathways that regulate host-commensal relationships and maintain intestinal homeostasis in the context of human health and IBD. Three specific aims of this project will determine (i) the innate mechanism by which ILCs regulate selective host-commensal relationships to maintain systemic immune cell homeostasis, (ii) mechanisms by which ILCs regulate host adaptive immune responses and maintain host- commensal relationships to prevent intestinal inflammation, and (i) whether the pathways regulating innate and adaptive host-commensal relationships are dysregulated and associated with disease severity in human IBD. Collectively, these studies will systematically interrogate the role and mechanisms by which ILCs maintain normal host-commensal relationships in basic mouse models and pioneer translational studies examining these pathways in human patients. I anticipate that defining the mechanistic contributions of ILCs to regulating selective host-commensal relationships could identify novel targets and direct the development of future preventative and therapeutic strategies to IBD and multiple other chronic human inflammatory diseases.

描述（由申请人提供）：人类免疫系统对于防止致病性微生物的感染至关重要。但是，对我们自己的组织或无害环境触发者（例如有益的共生细菌）的不当免疫反应可以促进自身免疫性或慢性炎症性疾病。实际上，在患者和鼠模型系统中的新兴研究表明，异常的宿主关系关系与许多慢性炎性疾病（例如炎症性肠病（IBD））相关或有因果关系。遗传关联和流行病学研究表明，IBD与先天性和适应性免疫反应失调相关，这些反应促进了失调的宿主相互作用和共生细菌驱动的慢性肠道炎症。最近的研究强调了先天淋巴样细胞（ILC）及其效应子细胞因子IL-22在调节肠炎中的作用。在新的初步研究中，我确定ILC对于通过解剖学限制了针对肠道相关淋巴组织（GALT）的健康哺乳动物的定义子集来维持选择性宿主关系至关重要。这种选择性调节可以通过两种机制进行。首先，IL-22细胞因子产生的先天途径有限的galt-居民共生细菌的外围传播，以防止全身性炎症。其次，ILC直接调节适应性免疫反应，并保持正常的宿主免疫反应对GALT居住的共生细菌，以防止肠道炎症。最后，我还观察到来自健康人类供体的肠样品中存在ILC，并且在IBD患者中与同一定义的galt-固定子集的子集相同的宿主 - 常见关系。我将采用这些强大的基本和转化的方法来描述规范宿主 - 惯常关系并在人类健康和IBD背景下维持肠道稳态的途径。该项目的三个具体目的将确定（i）ILC调节选择性宿主与承诺关系以保持系统性免疫细胞体内稳态的天生机制，（ii）ILCS通过该机制来调节宿主适应性免疫反应并维持宿主的宿主关系，并与宿主的关系保持较低的宿主关系，并与疾病相关性，并与疾病相关联，以及（i）适应性的疾病，以及（i）是否适应了疾病，（i）是否适应了疾病，以及（i）在人类IBD中。总的来说，这些研究将系统地询问ILC在基本小鼠模型和先驱翻译研究中维持正常的宿主关系的作用和机制，以检查人类患者的这些途径。我预计，定义ILC在调节选择性宿主 - 跨性别关系方面的机理贡献可以识别新的目标，并将未来预防和治疗策略的发展转化为IBD和多种其他慢性人类炎症性疾病。