Vascular Quiescence and Stabilization in Immunity

血管静止和免疫稳定

• 批准号: 8013874
• 负责人: Theresa T. Lu
• 金额: $ 43.44万
• 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/8013874
• 关键词: Attenuated; Autoimmune Diseases; 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，是功能正常的免疫系统的关键组成部分。在免疫反应期间，淋巴结脉管系统经历快速增殖扩张，随后血管成熟。虽然血管扩张的特点是不受调节的内皮细胞增殖、VCAM-1 表达和 HEV 运输效率以及血管周围成纤维细胞网状细胞组织的破坏，但随后的成熟阶段的特点是这些现象的逆转，从而促进血管静止和稳定。最近的研究已经开始描述免疫反应期间诱导淋巴结血管生长的机制，但调节随后的血管静止和稳定期的机制以及该过程的功能重要性尚不清楚。本申请旨在测试以下假设：树突状细胞亚群调节淋巴结中的血管静止和稳定，并且这种血管调节对于最佳免疫反应很重要。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反应的机制。我们将检查 B 细胞存活因子在淋巴结中是否更具限制性。 2）描述调节血管静止和稳定的分子介质。我们将使用允许有条件删除 CD11c+ 细胞中基因的小鼠。 3) 描述 FRC 组织的监管机制。我们将结合体外和体内技术来研究 FRC 表型的调节及其与 FRC 功能的关系。这些研究将产生有关树突状细胞功能、血管功能调节以及血管调节与免疫功能之间关系的新信息，并可能确定自身免疫和淋巴增殖性疾病的新靶标。 公共卫生相关性：血管为淋巴结提供营养，可能对控制免疫反应的正常发展很重要。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并发挥功能。这项研究对于制定新策略具有重要意义，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。