Lymphoid Tissue Microvessel Growth

在启动免疫反应时，淋巴结迅速而健壮地生长，这种生长是 伴随着血管的生长。血管对营养物质的供应和 调节进入淋巴结内的细胞运输。最近的研究已经开始描绘出 调节肿瘤中的血管生长和许多其他过程，这些研究已经导致 开发针对血管生长的药物。相比之下，淋巴中血管生长的调节 免疫应答过程中的结节和抗血管生成治疗作为免疫调节剂的潜在用途 都没有被很好地理解。这一应用提示研究淋巴血管的调节 通过测试在启动免疫反应时成熟的树突状细胞准备好 通过诱导血管生长，为即将扩张的淋巴结提供微环境。我们会 通过以下目的验证这一假说：1)确定刺激的树突状细胞影响 使用带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血管内皮生长因子水平的要求及成熟者血管生成潜能的评估 体外检测未成熟树突状细胞。2)确定以下各项的身份、法规和重要性 表达血管内皮生长因子的细胞，并利用血管内皮生长因子建立血管生长对免疫功能的重要性 记者小鼠，研究淋巴毒素的调节，并研究淋巴细胞与血管的运输 增长受阻。3)描绘了一种新的细胞类型的谱系和作用，该细胞类型既具有树突状细胞又具有 树突状细胞耗尽，抑制CCR2-/-小鼠单核细胞募集的内皮标记物，命运追踪 可能的骨髓前体细胞，并测试这些细胞的充分性。这些研究将产生新的成果 有关树突状细胞功能和控制淋巴血管生长的信息，并可能 对Castleman病、系统性红斑狼疮和 影响淋巴和淋巴血管生长的其他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开发。

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.