DEVELOPMENT AND FUNCTION OF INTESTINAL LYMPHOID TISSUES

肠淋巴组织的发育和功能

基本信息

批准号：
8537418
负责人：
Rodney D Newberry
金额：
$ 30.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8537418
关键词：
Activities of Daily Living Adult Appearance Area BLR1 gene CCR6 gene Cell Maturation Cell physiology Cells Cellular biology Chronic Data Dendritic Cells Dependence Development Epithelial Epithelium Gnotobiotic Grant Growth Factor Helper-Inducer T-Lymphocyte Homeostasis Human Immune system Immunology In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory disease of the intestine Intestines Investigation Lamina Propria Location Lymphoid Follicle Lymphoid Tissue Maintenance Mediating Modeling Mus Natural Killer Cells Nature Neonatal Phenotype Play Population Process Production Property Role Stimulus Surface System T-Lymphocyte Time base cell type chemokine cytokine fetal fetus cell in vitro Model in vivo interleukin-22 interleukin-23 precursor cell public health relevance repaired residence response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Recent studies identified a subset of NK cells associated with mucosal surfaces, or mucosal NK cells. These NK cells displayed multiple unique properties including the production of IL-22 to promote epithelial repair and homeostasis in response to proinflammatory cytokines, and accordingly these IL-22 producing NK cells have been demonstrated to play an important role in ameliorating intestinal inflammation. These mucosal NK cells are generated in response to inflammation and have an origin distinct from conventional NK cells. Moreover mucosal NK cells have a phenotype resembling the adult lymphoid tissue inducer (LTi) like cells that are responsible for the formation of solitary intestinal lymphoid tissues (SILT), including their developmental dependence upon the transcription factor ROR3t, and their residence within SILT in the uninflamed intestine. Based upon these observations and our preliminary data we hypothesize that during intestinal inflammation adult LTi like cells within the SILT differentiate into mucosal NK cells, subsequently mature in response to IL-21 produced by T-lymphocytes, and redistribute to the inflamed epithelium to produce IL-22 in response to IL-23 to mediate epithelial repair and maintenance. In specific aim 1 we will evaluate the ability of LTi like cells from the adult intestine to differentiate into mucosal NK cells and dendritic cells (DC) and evaluate the factors promoting mucosal NK cell and DC development. In specific aim 2 we will identify the role of SILT and luminal microbiota in the process of mucosal NK cell development and mucosal NK cell redistribution to the epithelium. In specific aim 3 we will evaluate the factors/cell types playing a role in mucosal NK cell maturation, redistribution, and IL-22 production. Findings from these studies will significantly increase our understanding of how the mucosal immune system facilitates epithelial barrier maintenance and repair during inflammation, and will open up new avenues of investigation for treatment of chronic inflammatory diseases of the intestine. PUBLIC HEALTH RELEVANCE: During intestinal inflammation a unique population of natural killer cells are generated. These cells produce cytokines promoting epithelial barrier maintenance and repair in response to inflammatory mediators. This proposal will investigate how these cells are generated and how they function to promote epithelial repair.

描述（由申请人提供）：最近的研究确定了与粘膜表面或粘膜NK细胞相关的NK细胞的子集。这些NK细胞表现出多种独特的特性，包括生产IL-22，以促进促炎细胞因子促进上皮修复和稳态，因此，这些IL-22产生的NK细胞已被证明在改善肠道炎症中起着重要作用。这些粘膜NK细胞是响应炎症而产生的，其起源与常规NK细胞不同。此外，粘膜NK细胞具有类似于成年淋巴组织诱导剂（LTI）的表型，例如负责形成孤立肠道淋巴组织（淤泥）的细胞，包括它们对转录因子ROR3T的发育依赖性及其在单个肠道内的堆积的依赖性。基于这些观察结果和我们的初步数据，我们假设在肠道炎症期间，成年成年LTI像淤泥中的细胞分化为粘膜NK细胞，随后响应于T- lymphocytes产生的IL-21而成熟，并以对IL-22的生产IL-22的炎症，以使IL-22的互联剂量为IL-23进行了Medialiatiatiatiatiatiatiation and-23。在特定目标1中，我们将评估LTI类似细胞从成年肠道分化为粘膜NK细胞和树突状细胞（DC）的能力，并评估促进粘膜NK细胞和DC发育的因素。在特定的目标2中，我们将确定淤泥和腔菌群在粘膜NK细胞发育和粘膜NK细胞重新分布到上皮细胞中的作用。在特定目标3中，我们将评估因子/细胞类型在粘膜NK细胞成熟，再分配和IL-22产生中起作用。这些研究的结果将大大提高我们对粘膜免疫系统如何促进炎症期间上皮屏障和修复的理解，并将为治疗肠道慢性炎症性疾病的新途径开放新的研究途径。公共卫生相关性：在肠道炎症期间，产生了独特的天然杀伤细胞。这些细胞产生细胞因子，以促进上皮屏障维持和修复，以响应炎症介质。该建议将研究这些细胞的产生方式以及它们如何发挥作用以促进上皮修复。