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.

Public Health Relevance

Blood vessels feed the lymph node and are likely to be important in controlling the normal development of an immune response. This research investigates how newly expanded blood vessels in the lymph node blood become stabilized and functional. This research has implications for development of new strategies to down regulate detrimental autoimmune responses in diseases such as lupus and to up regulate responses to vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079178-03
Application #
8213586
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Palker, Thomas J
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$434,363
Indirect Cost
$186,863
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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