Lymphoid Tissue Microvessel Growth

描述（由申请人提供）：淋巴结在免疫反应开始时迅速而强健地生长，这种生长伴随着血管的生长。血管是提供营养和调节细胞运输到淋巴结的关键。最近的研究已经开始描述肿瘤中血管生长的调节机制和许多其他过程，这些研究导致了针对血管生长的药物的开发。相比之下，免疫反应期间淋巴结血管生长的调节以及抗血管生成疗法作为免疫调节剂的潜在效用尚不清楚。本研究旨在通过验证以下假设来研究淋巴结血管生长的调控：在免疫反应启动时，成熟树突状细胞通过诱导血管生长为即将到来的扩张准备淋巴结微环境。我们将通过以下目标来验证这一假设：1)通过使用具有迁移缺陷的树突状细胞的小鼠，评估树突状细胞对淋巴结VEGF水平的需求，以及在体外测试中评估成熟和未成熟树突状细胞的血管生成潜力，确定受刺激的树突状细胞对内皮细胞增殖诱导的影响程度。2)利用VEGF-报告小鼠，研究淋巴毒素的调节作用，研究血管生长阻断剂对淋巴细胞运输的影响，确定VEGF表达细胞的身份、调控和重要性，并确定血管生长对免疫功能的重要性。3)通过树突状细胞耗竭、抑制CCR2-/-小鼠单核细胞募集、可能的骨髓前体的命运追踪和测试这些细胞的充分性，描绘具有树突状和内皮标记的新细胞类型的谱系和作用。这些研究将产生关于树突状细胞功能和淋巴结血管生长控制的新信息，并可能对理解和治疗Castleman病、系统性红斑狼疮和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具有指导意义。控制淋巴结血管的生长可能有助于控制淋巴结内自身免疫细胞或癌细胞的生长。这些研究将探讨调节淋巴结血管生长的机制，并可能导致淋巴瘤和免疫疾病的新疗法的发展。

DESCRIPTION (provided by applicant): Lymph nodes grow rapidly and robustly at the initiation 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 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.