Vascular Quiescence and Stabilization in Immunity

血管静止和免疫稳定

• 批准号: 7887391
• 负责人: Theresa T. Lu
• 金额: $ 43.76万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887391
• 关键词: Attenuated; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Blood; Blood Vessels; Cell Communication; Cell Proliferation; Cell Survival; Cell physiology; Cells; Data; Dendritic Cells; Development; Disease; Down-Regulation; Endothelial Cells; Ensure; Family; Fibroblasts; Functional disorder; Gene Deletion; Goals; Growth; High Endothelial Venule; Humoral Immunities; ITGAX gene; Immune; Immune response; Immune system; Immunity; In Vitro; Lupus; Lymphoid Tissue; Lymphoproliferative Disorders; Mediating; Mediator of activation protein; Micronutrients; Molecular; Mus; Oxygen; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Process; Proliferating; Regulation; Reporter; Research; Resolution; Reticular Cell; Role; Stromal Cells; T-Cell Development; TNF gene; Techniques; Testing; Vaccines; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factors; Work; attenuation; bevacizumab; feeding; immune function; in vivo; insight; lymph nodes; novel; public health relevance; response; trafficking

DESCRIPTION (provided by applicant): Lymph node blood vessels bring cells, oxygen, and micronutrients to the lymph node and are a critical component of a functioning immune system. During immune responses, the lymph node vasculature undergoes a rapid proliferative expansion followed by vascular maturation. While vascular expansion is characterized by unregulated endothelial cell proliferation, VCAM-1 expression, and HEV trafficking efficiency along with disrupted perivascular fibroblastic reticular cell organization, the subsequent maturation phase is characterized by reversal of these phenomena, thus promoting vascular quiescence and stabilization. Recent studies have begun to delineate the mechanisms involved in the induction of lymph node vascular growth during immune responses, but the mechanisms that regulate the subsequent period of vascular quiescence and stabilization and the functional importance of this process are not well understood. This application proposes to test the hypothesis that a dendritic cell subpopulation regulates vascular quiescence and stabilization in lymph nodes and that this vascular regulation is important for optimal immune responses. We will test the hypothesis via the following specific aims: 1) Delineate the mechanism by which vascular quiescence and stabilization promotes optimal immune responses. We will examine whether B cell survival factors are more limiting in lymph nodes. 2) Delineate the molecular mediators that regulate vascular quiescence and stabilization. We will use of mice that allow for conditional deletion of genes in CD11c+ cells. 3) Delineate the mechanisms by which FRC organization is regulated. We will use a combination of in-vitro and in-vivo techniques to examine the regulation of FRC phenotype and its relationship to FRC function. These studies will yield novel information on dendritic cell function, the regulation of vascular function, and the relationship between vascular regulation and immune function and may identify novel targets for autoimmune and lymphoproliferative diseases. PUBLIC HEALTH RELEVANCE: Blood vessels feed the lymph node and are likely to be important in controlling the normal development of an immune response. This research investigates how newly expanded blood vessels in the lymph node blood become stabilized and functional. This research has implications for development of new strategies to down regulate detrimental autoimmune responses in diseases such as lupus and to up regulate responses to vaccines.

描述（由申请人提供）：淋巴结血管将细胞、氧气和微量营养素带到淋巴结，是功能免疫系统的关键组成部分。在免疫应答期间，淋巴结脉管系统经历快速增殖性扩张，随后是血管成熟。虽然血管扩张的特征在于不受调节的内皮细胞增殖、VCAM-1表达和HEV运输效率沿着破坏的血管周围成纤维细胞网状细胞组织，但随后的成熟阶段的特征在于这些现象的逆转，从而促进血管静止和稳定。最近的研究已经开始描绘参与诱导淋巴结血管生长的免疫反应过程中的机制，但调节随后的血管静止期和稳定的机制和功能的重要性，这一过程还没有得到很好的理解。本申请提出测试树突状细胞亚群调节淋巴结中的血管静止和稳定以及这种血管调节对于最佳免疫应答是重要的这一假设。我们将通过以下具体目标来检验这一假设：1）描述血管静止和稳定促进最佳免疫应答的机制。我们将研究B细胞存活因子是否在淋巴结中更具限制性。2)描述调节血管静止和稳定的分子介质。我们将使用允许条件性缺失CD 11 c+细胞中基因的小鼠。3)描述监管家庭团聚委员会组织的机制。我们将使用体外和体内技术的组合来检查FRC表型的调节及其与FRC功能的关系。这些研究将产生新的信息树突状细胞的功能，调节血管功能，血管调节和免疫功能之间的关系，并可能确定新的目标，自身免疫性和淋巴增生性疾病。 公共卫生相关性：血管滋养淋巴结，可能在控制免疫反应的正常发展方面很重要。这项研究调查了淋巴结血液中新扩张的血管如何变得稳定和功能。这项研究对开发新的策略具有重要意义，这些策略可以下调狼疮等疾病中有害的自身免疫反应，并上调对疫苗的反应。