LIGHT is a member of the tumor necrosis factor super family that engages two receptors, the lymphotoxin B receptor (LTBR) and the herpes virus entry mediator (HVEM). Over expression of LIGHT by transgenic mouse T cells causes colitis. We have made the surprising observation, however, that the absence of LIGHT expression in immune deficient Rag-/- mice leads to increased colitis in the T cell transfer model. The experiments in this application are designed to understand the surprising anti-inflammatory role of LIGHT expression in preventing severe colitis. Our preliminary data indicate that LIGHT acts in the innate Immune system by binding to the LTBR. Based on our data and published literature, we propose that LIGHT expression by macrophages acts on the LTBR also expressed by these cells to promote their apoptosis, thereby limiting inflammation. We will use a combination of Immunologic and genetic methods to test our hypothesis and to understand the unexpected role of LIGHT expression by cells other than T lymphocytes in the prevention of severe colitis.
In aim 1, we will characterize the immunopathogenesis of the severe colitis in Rag-/- recipient mice deficient for LIGHT. We also will analyze the effects of reduced LIGHT expression in models of colitis that involve only innate immune cells, and we will determine if the absence of LIGHT affects apoptosis of some cell type, a known outcome of the LIGHT:LTBR Interaction.
In aim 2 we will confirm (or refute) the preliminary data indicating that prevention of severe colitis is dependent upon LTBR expression.
In aim 3 we will determine if soluble LIGHT Is required, as It Is In concanavalin A-induced liver damage. Experiments in aim 4 will determine the critical cell types that must express LIGHT and its receptor in order to prevent severe disease. Finally, experiments in Aim 5 will bridge the findings from mouse models to the study of patients. We will investigate TNFSF14 (LIGHT) gene polymorphisms that affect colitis pathogenesis In IBD patients, to determine if these are related either to LIGHT expression levels or to the ability of LIGHT to bind its receptors. Therefore, the experiments in this project should lead to great Insights into the mechanism underlying severe colitis in the absence of LIGHT expression.
LIGHT expression by human T cells is related to IFNy synthesis and LIGHT expression is higher in the inflamed regions of the intestine of IBD patients. Therefore, antibody blockade of LIGHT is a promising therapeutic currently under development. In animal model of colitis, however, we have found that LIGHT expression by cells other than T cells has an anti-inflammatory role. It is important to determine how LIGHT both promotes and prevents severe disease so that It can be targeted more effectively.
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