The goal of these studies is to gain an understanding of lymphoid organ development and function in embryonic development and in chronic inflammation. Simultaneous expression of LTa and LTb results in the formation of ectopic lymphoid aggregates with the characteristics of lymphoid organs arising through a process termed lymphoid organ neogenesis. These """"""""tertiary lymphoid organs"""""""" (TLOs) are seen in autoimmunity, including the early stages of insulin dependent diabetes mellitus (IDDM). TLOs provide information about autoimmunity and serve as models of normal lymphoid development. Studies with transgenic and knock out mice and spontaneous models of autoimmunity have identified the crucial and differential roles of cytokines LTa and the LTab complex in regulation of inflammation and lymphoid organ development, particularly high endothelial venules (HEVs). This renewal application will continue to elucidate the regulation of HEVs and lymphatic vessels (LVs). HEV genes are regulated in development, in TLOs, and in acute inflammation. The mature HEV phenotype depends on signaling through the LTb receptor. Peripheral lymph node HEVs revert transiently to an immature phenotype and permanently if lymphatic vessels are severed, suggesting a requirement for """"""""lymphatic factors"""""""" during their maintenance. Thus understanding LV regulation is a crucial aspect of understanding HEV regulation. Several hypotheses will be tested. Hypothesis I. TLOs represent sites of antigen presentation, with LVs and HEVs, and are valid models to study lymphoid organ development. Hypothesis II. Lymphatic vessels are regulated by the LT family and are initiators of lymphoid organs. Hypothesis III. Continual signaling through TNFR and/or LTbR is necessary for maintenance and function of lymphoid organs and HEVs and LVs.
The specific aims to test these hypotheses are to: 1. Determine whether the LT induced TLO is a valid model of lymphoid organogenesis. 2. Determine how HEVs and LVs are regulated. 3. Determine if LT is necessary and sufficient for lymphangiogenesis. 4. Determine if continual LT signaling is necessary to maintain HEVs and lymphatic vessel function. These studies are important as they elucidate specific aspects of LN development. Understanding HEV and LV regulation could provide useful strategies for inhibiting TLOs in autoimmunity. ? ? ?
