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

• 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
• 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

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）：人体免疫系统对防止病原微生物感染至关重要。然而，针对我们自身组织或非有害环境触发因素（如我们周围有益的共生细菌）的不适当免疫反应会促进自身免疫或慢性炎症性疾病。事实上，对患者和小鼠模型系统的新研究表明，异常的宿主-共生关系与许多慢性炎症性疾病（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与先天和适应性免疫反应失调有关，这些免疫反应会促进宿主-共生相互作用失调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ILCs通过解剖学上限制健康哺乳动物肠道相关淋巴组织（GALT）的特定共生细菌子集，对维持选择性宿主-共生关系至关重要。这种选择性监管可以通过两种机制发生；首先，IL-22细胞因子产生的先天途径限制了GALT共生菌的外周传播，以防止全身性炎症。第二，ILCs直接调节适应性免疫反应，维持宿主对galt共生菌的正常免疫反应，预防肠道炎症。最后，我还观察到来自健康人类供体的肠道样本中存在ilc，以及IBD患者中与GALT常驻共生菌相同定义亚群的宿主-共生关系失调。我将使用这些强大的基础和转化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稳态的途径。该项目的三个具体目标将确定(i) ILCs调节选择性宿主-共生关系以维持全身免疫细胞稳态的先天机制，（ii） ILCs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)调节先天和适应性宿主-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。总的来说，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，并在人类患者中探索这些途径的先驱转化研究。我预计，确定ilc对调节选择性宿主-共生关系的机制贡献可以确定新的靶点，并指导未来IBD和多种其他慢性人类炎症性疾病的预防和治疗策略的发展。