, OVERALL 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. 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. Directed by Dr. Charles Elson, we 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. Headed by Dr. Robin Lorenz, we will use the mdr1alpha knockout model to define how the host epithelium and other innate immune cells detect and respond to the microbiota. Headed by Dr. Casey Weaver, we 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 IFNgamma play in establishing the balance between pathogenic and regulatory T cell responses. Led by Dr. Stephan Targan, located at Cedars-Sinai Medical Center in Los Angeles, CA, will lead the utilization of a large panel of patient materials to define the innate and adaptive immune response in patients with Crohn's disease who are reactive to CBiM flagellin, as well as their clinical phenotypes and genotypes, to test the hypothesis that these patients represent a distinct patient subset. This research will provide administrative support and coordination, and an Animal Model at U.A.B. which will centralize the production of mice with experimental colitis, provide for a central pathologic analysis, and generate stocks of genetically modified mice for use. This is designed to accelerate the transfer of information discovered from basic labs to the clinic and vice versa. The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develoo better diaanostic and therapeutic strateaies for patients.
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