INTESTINAL IMMUNE SYSTEM IN HOST-ENVIRONMENT INTERACTION

总体描述(由申请人提供)： 该计划项目的中心主题是确定肠道粘膜对肠道微生物和微生物产品的先天和后天免疫反应的机制，以及随后的粘膜保护性免疫和炎症反应。这四个相互关联的研究项目具体涉及上皮细胞和树突状细胞之间以及树突状细胞和T细胞之间的通讯调节，这些通讯发生在粘膜动态平衡和保护性免疫期间。在新的体内和体外小鼠模型系统中，模型肠道病原体被用来探测粘膜细胞的反应。该项目汇集了来自医学系、病理学和神经科学系以及加州大学圣迭戈分校拉霍亚过敏和免疫学研究所的经验丰富的研究人员。研究人员在细胞和分子粘膜免疫学、粘膜炎症、细胞信号和微生物发病机制方面拥有重要的专业知识，并有协作互动的记录。研究单位1研究结肠和小肠中树突状细胞(DC)和上皮细胞对先天性粘膜免疫反应的调节。单元1使用附着和消除病变诱导的肠道病原体和轮状病毒来探测宿主的反应，以及粒细胞-巨噬细胞集落刺激因子决定肠道感染结局的机制。研究单位2调查肠道粘膜反应，以贾第虫为模型原生动物病原体，在没有粘膜炎症的情况下产生强大的保护性免疫，以确定对微创肠道病原体的免疫防御。研究单位3研究粘膜佐剂如何超越T调节细胞的耐受诱导效应并激发效应者T细胞免疫反应，重点是霍乱毒素和Th17在体外和体内的分化。研究单元4是该计划的新成员，负责研究维甲酸通过其对DC和T细胞的活性来决定正常粘膜稳态和保护性免疫之间的平衡的机制。研究项目得到了四个核心的支持：一个老鼠模型核心，一个组织病理学核心，一个成像和细胞分类核心和一个管理核心。

DESCRIPTION, OVERALL (provided by applicant): The central theme of the Program Project Is focused on mechanisms that determine innate and acquired immune responses in the intestinal mucosa to enteric microbes and microbial products, and the consequent mucosal protective immune and inflammatory responses. The four interrelated research projects specifically address the regulation of communication between epithelial cells and dendritic cells, and between dendritic cells and T cells, which takes place during mucosal homeostasis and protective immunity. Model enteric pathogens are used to probe mucosal cellular responses in novel in vivo and in vitro murine model systems. The program brings together experienced investigators from the Departments of Medicine, Pathology, and Neurosciences and the UCSD campus based La Jolla Institute for Allergy and Immunology. The investigators have a record of significant expertise in cellular and molecular mucosal immunology, mucosal inflammation, cell signaling and microbial pathogenesis, and a record of collaborative interactions. Research Unit 1 investigates the regulation of innate mucosal immune responses by dendritic cells (DC) and epithelial cells in the colon and small intestine. Unit 1 uses an attaching and effacing lesion-inducing enteric pathogen and rotavirus to probe the host response, and the mechanisms by which granulocyte-macrophage colony stimulating factor determines the outcome of enteric infection. Research Unit 2 investigates intestinal mucosal responses that determine immune defenses against minimally invasive enteric pathogens, using Giardia as a model protozoan pathogen that elicits strong protective immunity in the absence of mucosal inflammation. Research Unit 3 investigates how mucosal adjuvants override the tolerance-inducing effects of T regulatory cells and provoke effector T cell immune responses, with a focus on cholera toxin and Th17 differentiation in vitro and in vivo. Research Unit 4, which is new to the Program with the renewal application, investigates mechanisms by which retinoids determine the balance between normal mucosal homeostasis and protective immunity through their activity on DC and T cells. The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core.