Human intestinal inflammatory diseases are driven processes mediated by a dysregulated adaptive immune response in the intestine. It is well accepted that the basal immunologic tone of the intestine is characterized by tolerogenic responses manifested by the production of cytokines by immunomodulatory (non-T helper 1) T-lymphocytes. Despite the recognized dictomy of T helper subset responses, and the recognition of the predominance of non-T helper 1responses in the uninflamed intestine, it is not understood why one T helper subset phenotype would predominate over another baseline in the intestine. We have demonstrated a role for cyclooxygenase- 2 (COX-2) dependent arachidonic acid (AA) metabolites produced by the small intestine lamina propria in prevention of an inflammatory response to dietary antigen. Under the auspices of the currently funded K08 award (DK-02608) we have generated data demonstrating spontaneous and continuous production of (COX-2) dependent metabolites by a subset of lamina propria stromal cells. These observations support our hypothesis that lamina propria stromal cells play a role in directing the adaptive immune response to luminal antigens. To expand upon the observations obtained under the K08 award and to gain a better understanding of the role of lamina propria stromal cells in the immune response to luminal antigens, we propose the following specific aims: 1) Develop and characterize clonal populations of lamina propria stromal cells. 2) Evaluate the ability of lamina propria stromal cells to influence helper T-lymphocyte responses. Completion of these specific aims will involve characterizing clonal populations of lamina propria stromal cells with respect to the production immunologically relevant molecules, and identifying the physical location of these lamina propria stromal cells within the intestine. Heterogeneous populations of lamina propria stromal cells and clonal populations of lamina propria stromal cells will be analyzed for their ability to influence antigen specific T-lymphocyte responses. These findings will allow identification of subsets of lamina propria stromal cells with the ability to influence immune response in the intestine, and will direct future studies examining changes in the predominance of these stromal cells in animal models of intestinal inflammation.
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| Lorenz, Robin G; Chaplin, David D; McDonald, Keely G et al. (2003) Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J Immunol 170:5475-82 |
