? The inflammatory bowel diseases (IBD) remain complex disorders, but over the past decade experimental models of IBD have advanced our understanding of some of the cellular and molecular mechanisms important in their pathogenesis. These models have shown that CD4 T cells are the effector cells mediating disease in most instances, that the enteric bacterial flora drives this pathogenic response, and that the innate immune system (epithelium, dendritic cells, macrophages) is a critical link between these two elements. Thus, the interaction of the innate and adaptive immune response with the microbiota and their products is the major focus of this Program Project. We have assembled novel tools, technologies, and reagents from microbial, mouse, and human sources that make possible substantive questions to be addressed and interesting hypotheses to be answered. Among these resources is a panel of immunodominant microbial antigens, particularly bacterial flagellins, which have been shown to stimulate immune responses in multiple mouse models and in a subset of patients with Crohn's disease. The Program Project will be directed by Dr. Charles Elson and will consist of four projects and two cores. Project 1, headed by Dr. Charles Elson, will use flagellins as probes of the innate and adaptive immune response to the microbiota in C3H and B6 mice, will define for the first time whether epitope spreading of the immune response to microbial antigens occurs in IBD and is related to its progression, and will define where and how pathogenic T cells are sensitized in colitic mice. Project 2, headed by Dr. Robin Lorenz, will use the mdrla knockout model to define how the host epithelium and other innate immune cells detect and respond to the microbiota. Project 3 will be headed by Dr. Casey Weaver and will use novel transgenic cytokine reporter mouse lines to study the adaptive T cell response to the microbiota and particularly the roles IL-23 versus IL-12, and IL-17 versus IFNy play in establishing the balance between pathogenic and regulatory T cell responses. Project 4, led by Dr. Stephan Targan, is located at Cedars-Sinai Medical Center in Los Angeles, CA. This project will utilize a large panel of patient materials to define the innate and adaptive immune response in patients with Crohn's disease who are reactive to CBirl flagellin, as well as their clinical phenotypes and genotypes, to test the hypothesis that these patients represent a distinct patient subset. These projects are supported by an Administrative Core and an Animal Model Core at U.A.B. This supplemental application is for funds to continue the translational studies represented in Project 4 in years 4 and 5. The continuation of these studies in humans is critical to the long-term goal of increasing our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients. ? ?
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