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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：
8715434
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：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715434
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 Interferons 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(申请人提供)：人体免疫系统对防止感染病原微生物至关重要。然而，针对我们自身组织的不适当的免疫反应或无害的环境触发因素，如我们周围有益的共生细菌，可能会促进自身免疫或慢性炎症性疾病。事实上，在患者和小鼠模型系统中的新研究表明，异常的宿主-共生关系与许多慢性炎症性疾病相关或因果联系，例如炎症性肠病(IBD)。遗传关联和流行病学研究表明，IBD与调节失调的先天和获得性免疫反应有关，这些反应促进了调节失调的宿主-共生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(ILCs)及其效应细胞因子IL-22在调节肠道炎症中的作用。在新的初步研究中，我发现ILC对维持选择性宿主-共生关系至关重要，因为它在解剖学上将定义的共生细菌亚集限制在健康哺乳动物的肠道相关淋巴组织(GALT)。这种选择性的调节可能通过两种机制发生：第一，IL-22细胞因子产生的固有途径限制了GalT驻留的共生细菌的外周传播，以防止全身炎症。第二，ILCs直接调节适应性免疫反应，并维持宿主对GalT共生菌的正常免疫反应，以防止肠道炎症。最后，我还观察到来自健康人类捐赠者的肠道样本中存在ILC，以及IBD患者中与同一定义的GalT驻留共生菌亚集的失调宿主-共生关系。我将使用这些强大的基本和翻译方法来描述在人类健康和IBD的背景下调节宿主-共生关系和维持肠道内稳态的途径。本项目的三个具体目标将确定(I)ILC调节选择性宿主-共生关系以维持全身免疫细胞稳态的固有机制，(Ii)ILC调节宿主适应性免疫反应和维持宿主-共生关系以预防肠道炎症的机制，以及(I)调节固有和适应性宿主-共生关系的途径是否失调并与人类IBD的疾病严重程度相关。总而言之，这些研究将系统地询问ILC在基本小鼠模型中维持正常宿主-共生关系的作用和机制，以及在人类患者中检验这些途径的开创性翻译研究。我预计，确定ILC对调节选择性宿主-共生关系的机械贡献可以确定新的靶点，并指导未来预防和治疗IBD和其他多种人类慢性炎症性疾病的策略的发展。