Previous studies have shown alterations in T cell signaling mechanisms contributing to depressed cell mediated immunity in burn, trauma, and septic injury conditions. The signaling alterations could result from the action of inhibitory mediators such as PGE2, TGF-beta and IL-10 released systemically and/or within the peripheral and/or mucosal lymphoid organs. We hypothesize that altered peripheral lymphoid T cell signaling results from modulations in the mucosal T cell systems during the injury-induced invasion of intestinal mucosa by indigenous bacteria from the GI tract. The present studies will evaluate signaling events and effector responses of T cells from intestinal tissues of burn and burn-plus-infection rats. The T cell modulations will be correlated with mucosal invasion by bacteria and their product. The role of the gut-derived mediators and bacteria/bacterial product will be evaluated in the suppression of T cell in mesenteric lymph node and spleen. Experiments are planned also to determine the feasibility of IL-10 and TGF-beta gene manipulation in the intestinal mucosa to up- and down-regulate the signaling and response behavior in intestinal and peripheral lymphoid tissue T-cells.
Specific Aim 1 is to delineate activation of kinases (p59fyn, p56lck, Zap70, Erk, JNK), Ca2+ mobilization, and regulation of nuclear factors and proliferation/IL2 expression in T cells from intestinal epithelium, lamina propria, and Peyer's patches.
Specific Aim 2 is to correlate injury-induced modulations in intestinal and peripheral T cells with mucosal invasion by Escherichia coli.
Specific Aim 3 is to evaluate effects of PGE2, TGF-beta and IL-10, released by the various intestinal epithelial/accessory cells on signaling and response elicitation by mucosal T cell populations, as well as T cells from peripheral lymph nodes (MLN and spleen). The use of PGE2 inhibitors, anti IL-10 and anti TGF-beta antibodies will allow for the determination of specific inhibitory effects on T cell modulations.
Specific Aim 4 is to determine the migration potential of intestinal T cells to intestinal and peripheral lymphoid tissues in the injury states. These experiments will quantify adhesion capability of T cells of intestinal origin.
Specific Aim 5 is to manipulate IL-10 and TGF-beta genes in the intestinal tissue by the infusion of adenovirus vectors to up- and down-regulate these genes to determine the critical inhibitory role of the gene products and to explore potential therapeutic strategies of gene manipulation in injury conditions. These studies will yield novel information on the role of intestinal immune modulations on systemic immune suppression due to mucosal invasion by indigenous bacteria during acute burn/infection injury. The demonstration of intestinal mucosal immune modulation as the initiating event in the injury-induced immunosuppression could allow us to direct immunomodulatory therapy to the GI lumen of injured hosts.
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