Lymphoid Tissue Microvessel Growth

淋巴结在免疫应答开始时快速且稳健地生长，并且这种生长是免疫应答的一部分。 伴随着血管的生长。血管对于提供营养和 调节进入淋巴结的细胞运输。最近的研究已经开始描绘的机制， 调节肿瘤和许多其他过程中的血管生长，这些研究已经导致 开发针对血管生长的药物。相反，淋巴管中血管生长的调节 免疫应答期间的节点和抗血管生成疗法作为免疫调节剂的潜在效用 并没有得到很好的理解。本申请提出研究淋巴结血管的调节， 通过测试免疫反应启动时成熟的树突状细胞准备的假设来实现生长 通过诱导血管生长来改善淋巴结微环境，以促进即将到来的扩张。我们将 通过这些目的来测试这一假设：1）确定刺激的树突状细胞影响细胞增殖的程度。 通过使用具有迁移缺陷树突状细胞的小鼠诱导内皮细胞增殖，评估 树突状细胞对淋巴结VEGF水平的要求，并评估成熟的血管生成潜力。 和未成熟的树突细胞。2)确定以下各项的身份、规定和重要性： 表达VEGF的细胞，并通过使用VEGF- 报告小鼠，研究光毒素的调节，并研究淋巴细胞运输与血管 生长阻滞。3)描述一种新的细胞类型的谱系和作用， 树突状细胞耗竭的内皮标志物，抑制CCR 2-/-小鼠中单核细胞募集，命运追踪 可能的骨髓前体细胞，并测试这些细胞的充足性。这些研究将产生新的 关于树突状细胞功能和关于淋巴结血管生长的控制的信息， 对理解和治疗Castleman病，系统性红斑狼疮， 其他影响淋巴结和淋巴结血管生长的淋巴增生性和自身免疫性疾病。 控制淋巴结血管生长可能有助于控制自身免疫性或 淋巴结中的癌细胞这些研究将探讨调节淋巴结的机制 血管生长，并可能导致淋巴瘤和免疫疾病的新疗法的发展。

Lymph nodes grow rapidly and robustly at the inititation of an immune response and this growth is accompanied by growth of its blood vessels. The blood vessels are critical for supplying nutrients and for regulating cell trafficking into the lymph node. Recent studies have begun to delineate the mechanisms that regulate vascular growth in tumors and in a number of other processes, and these studies have led to development of drugs that target vascular growth. In contrast, the regulation of vascular growth in the lymph node during immune responses and the potential utility of anti-angiogenic therapies as immune modulators are not well understood. This application proposes to investigate the regulation of lymph node vascular growth by testing the hypothesis that, at the initiation of an immune response, mature dendritic cells prepare the the lymph node microenvironment for the forthcoming expansion by inducing vascular growth. We will test this hypothesis via these aims: 1) Determine the extent to which stimulated dendritic cells influences the induction of endothelial proliferation by using mice with migration-defective dendritic cells, assessing the requirement for dendritic cells on lymph node VEGF levels, and assessing the angiogenic potential of mature and immature dendritic cells in in-vitro assays. 2) Establish the identity, regulation, and importance of VEGF-expressing cells and establish the importance of vascular growth to immune function by using VEGF- reporter mice, investigating regulation by lymphotoxin, and investigating lymphocyte trafficking with vascular growth blockade. 3) Delineate the lineage and role of a novel cell type that bears both dendritic and endothelial markers by dendritic cell depletion, inhibiting monocyte recruitment in CCR2-/- mice, fate tracing of likely bone marrow precursors and testing the sufficiency of these cells. These studies will yield novel information about dendritic cell functions and about the control of lymph node vascular growth and may have implications for understanding and treatment of Castleman's disease, systemic lupus erythematosus, and other lymphoproliferative and autoimmune diseases that affect lymph node and lymph node vascular growth. Controlling lymph node blood vessel growth can potentially help to control growth of autoimmune or cancer cells in the lymph node. These studies will investigate the mechanisms that regulate lymph node vessel growth and may lead to the development of new therapies for lymphomas and immune diseases.