Vascular Quiescence and Stabilization in Immunity

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，是正常运作的免疫系统的关键组成部分。在免疫反应期间，淋巴结血管系统经历快速的增殖扩张，随后血管成熟。血管扩张的特征是血管内皮细胞无调控的增殖、VCAM-1的表达和HEV的转运效率以及血管周围成纤维细胞网状细胞结构的破坏，而随后的成熟阶段的特征是这些现象的逆转，从而促进血管的平静和稳定。最近的研究已经开始描述在免疫反应中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这一过程的功能重要性还不是很清楚。这项应用提出了一项假设，即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是重要的。我们将通过以下具体目标来检验这一假说：1)描绘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局限性。2)阐明调节血管静止和稳定的分子介质。我们将使用允许有条件地删除CD11c细胞中基因的小鼠。3)界定财务汇报局组织的监管机制。我们将使用体外和体内技术相结合的方法来研究FRC表型的调节及其与FRC功能的关系。这些研究将在树突状细胞功能、血管功能的调节以及血管调节和免疫功能之间的关系方面产生新的信息，并可能确定自身免疫和淋巴增生性疾病的新靶点。

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.