Vascular Quiescence and Stabilization in Immunity

描述（由申请人提供）：淋巴结血管将细胞、氧气和微量营养素输送到淋巴结，是免疫系统功能的重要组成部分。在免疫应答过程中，淋巴结血管经历快速增殖扩张，随后血管成熟。血管扩张的特征是内皮细胞增殖、VCAM-1表达和HEV运输效率不受调节，以及血管周围成纤维网状细胞组织被破坏，而随后的成熟阶段的特征是这些现象的逆转，从而促进血管的静止和稳定。最近的研究已经开始描述免疫应答期间诱导淋巴结血管生长的机制，但调节随后血管静止和稳定时期的机制以及这一过程的功能重要性尚未得到很好的理解。该应用程序旨在验证树突状细胞亚群调节淋巴结血管静止和稳定的假设，并且这种血管调节对最佳免疫反应很重要。我们将通过以下具体目标来验证这一假设：1)描述血管静止和稳定促进最佳免疫反应的机制。我们将研究B细胞存活因子是否在淋巴结中更受限制。2)描述调节血管静止和稳定的分子介质。我们将使用允许在CD11c+细胞中条件删除基因的小鼠。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。这些研究将产生关于树突状细胞功能、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.