The inflammatory bowel diseases (IBD) involve complex abnormalities in the innate and adaptive immune response to the Intestinal microbiota. Data from experimental models has found that CD4 T cells are the effector cells mediating disease in most instances, that the enteric bacterial flora drives this pathologic response, and that the innate immune system (epithelium, dendritic cells, macrophages) is a critical link between these two elements. Thus, the major focus of this Program Project is on the interaction of the innate and adaptive immune responses with the microbiota and its products and on the genes that affect these interactions. The Program Project will be directed by Dr. Charles Elson and will consist of four Projects and two Cores. Project 1, headed by Dr. Elson, will use flagellins as probes of the normal T cell homeostatic response in the intestine. Studies will address the hypothesis that CD4 T cell effector subsets in the intestine maintain homeostasis by a number of different pathways that can compensate for one another, that these pathways have limits beyond which intestinal inflammation results, and that homeostasis can be restored by augmentation of regulatory T cells. Project 2, headed by Dr. Robin Lorenz, will use the mdr1a knockout model to address the hypothesis that the absence of the mdr1a encoded membrane pump leads to dysfunctional handling of xenobiotics, which results in abnormal development and function in cell types that express the aryl hydrocarbon receptor resulting in spontaneous. Project 3 will be headed by Dr. Casey Weaver who will continue his studies on Th17 cells in the intestine and their role in IBD and will use novel cytokine reporter and other mutant mouse lines to test the hypothesis that Th17 and "Th1-like" cells cooperate to sustain intestinal inflammation to intestinal microbiota antigens in IBD, that both cell types emerge from a common early Th17 developmental pathway, and that IL-23-dependent memory Th17 cells are required for sustained IBD pathogenesis. Project 4 is led by Dr. Stephan Targan at Cedars-Sinai Medical Center in Los Angeles, CA. This Project will continue to utilize a large panel of patient materials to define the Innate and adaptive Immune response in patients with Crohn's disease who have seroreactivity to CBir1 flagellins to test the hypothesis that immune response to CBIr1 flagellin defines a population of patients with genetic variations of the IL-23, IL-17, and IL-22 pathways, as well as variations in TL1A gene expression, resulting In a severe disease course in IBD. These Projects will be supported by an Administrative Core which will provide administrative support and coordination, and an Animal Model Core 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 stocks of mice for use in the Projects. The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients.
Inflammatory bowel disease afflicts 1.4 million Americans. The proposal will increase our understanding of the immune mechanisms underlying IBD in order to develop better diagnostic and therapeutic strategies for patients.
|Balasubramani, Anand; Winstead, Colleen J; Turner, Henrietta et al. (2014) Deletion of a conserved cis-element in the Ifng locus highlights the role of acute histone acetylation in modulating inducible gene transcription. PLoS Genet 10:e1003969|
|Wang, Yan; Godec, Jernej; Ben-Aissa, Khadija et al. (2014) The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-?-producing T helper 17 cells. Immunity 40:355-66|
|Wolf, Kyle J; Daft, Joseph G; Tanner, Scott M et al. (2014) Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice. J Histochem Cytochem 62:237-50|
|Alexander, Katie L; Targan, Stephan R; Elson 3rd, Charles O (2014) Microbiota activation and regulation of innate and adaptive immunity. Immunol Rev 260:206-20|
|Cao, Anthony T; Yao, Suxia; Stefka, Andrew T et al. (2014) TLR4 regulates IFN-? and IL-17 production by both thymic and induced Foxp3+ Tregs during intestinal inflammation. J Leukoc Biol 96:895-905|
|Staley, Elizabeth M; Tanner, Scott M; Daft, Joseph G et al. (2013) Maintenance of host leukocytes in peripheral immune compartments following lethal irradiation and bone marrow reconstitution: implications for graft versus host disease. Transpl Immunol 28:112-9|
|Basu, Rajatava; Hatton, Robin D; Weaver, Casey T (2013) The Th17 family: flexibility follows function. Immunol Rev 252:89-103|
|Viaud, Sophie; Saccheri, Fabiana; Mignot, Gregoire et al. (2013) The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971-6|
|Zindl, Carlene L; Lai, Jen-Feng; Lee, Yun Kyung et al. (2013) IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci U S A 110:12768-73|
|Hepworth, Matthew R; Monticelli, Laurel A; Fung, Thomas C et al. (2013) Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498:113-7|
Showing the most recent 10 out of 50 publications