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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Study Section
Special Emphasis Panel (ZDK1-GRB-7 (M1))
Program Officer
Hamilton, Frank A
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhao, Qing; Harbour, Stacey N; Kolde, Raivo et al. (2017) Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota. J Immunol 199:312-322
Cao, Wei; Kayama, Hisako; Chen, Mei Lan et al. (2017) The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids. Immunity 47:1182-1196.e10
Tanner, Scott M; Daft, Joseph G; Hill, Stephanie A et al. (2016) Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer. J Histochem Cytochem 64:753-767
Daft, Joseph G; Lorenz, Robin G (2015) Role of the gastrointestinal ecosystem in the development of type 1 diabetes. Pediatr Diabetes 16:407-18
Harbour, Stacey N; Maynard, Craig L; Zindl, Carlene L et al. (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112:7061-6
Basu, Rajatava; Whitley, Sarah K; Bhaumik, Suniti et al. (2015) IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat Immunol 16:286-95
Hepworth, Matthew R; Fung, Thomas C; Masur, Samuel H et al. (2015) Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4? T cells. Science 348:1031-5
Pike, Brian L; Paden, Katie Ann; Alcala, Ashley N et al. (2015) Immunological Biomarkers in Postinfectious Irritable Bowel Syndrome. J Travel Med 22:242-50
Christmann, Benjamin S; Abrahamsson, Thomas R; Bernstein, Charles N et al. (2015) Human seroreactivity to gut microbiota antigens. J Allergy Clin Immunol 136:1378-86.e1-5
Singer, Jeffrey R; Weaver, Casey T (2015) Daughter's Tolerance of Mom Matters in Mate Choice. Cell 162:467-9

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