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.
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