The basic pathogenetic mechanisms involve in inflammatory bowel disease (IBD) remain elusive. However, like other chronic inflammatory diseases, the pathogenesis appears to be multi-factorial and particularly involve complex interactions among genetic environmental and immunologic factors. The scientific fields of immunology and genetics are thought to most likely hold the answer to the puzzle of IBD and these are the major areas of investigation in this Program Project. The basic themes of this proposal thus relate to the immunologic mechanisms determining chronic inflammation in the intestine, the induction and regulation of the mucosal immune system, especially mucosal responses to enteric bacterial antigens,. The mechanisms of antigen handling in the intact and inflamed colon, and the genetic influences that determine susceptibility to disease. The strategy has been and will continue to be focused on newly developed mouse models of colitis. Although no model exactly duplicates human IBD, models can allow important insight into disease mechanisms. The mouse has been chosen because of the rich array of techniques and reagents available only in this species in both immunology and genetics. 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 focus on T cells reactive with antigens in the enteric bacterial flora, whether intestinal bacterial antigens induce tolerance or immunity, and the regulatory T cells that limit pathogenic responses in the intestinal, particularly Tr1 cells. Project 2, headed by Dr. Jerry McGhee, will explore Project 3, headed by Dr. Casey Weaver, using a noel antigen-specific model system, will address antigen interactions that maintain normal mucosal homeostasis and thus prevent chronic intestinal inflammation. Project 4, headed by Dr. Edward Leiter, is located at the Jackson Laboratory in Bar Harbor, ME. This project will map genes important in susceptibility to colitis using C3H/HeJBir.IL-10-/- and C57BL/6.IL-10-/- strains. These projects will be supported by an Administrative Core which will provide administrative support and coordination, and an pathogenic analysis, and generate stocks of genetically modified mice for us in the projects. The long-term goal of this Program Project is to increase our understanding of the fundamental mechanisms of chronic intestinal inflammation to develop between therapies for patients with IBD, such as the manipulation of intestinal immune cells and functions to prevent or inhibit disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK044240-09
Application #
2893764
Study Section
Special Emphasis Panel (ZDK1-GRB-C (M1))
Program Officer
Hamilton, Frank A
Project Start
1991-09-01
Project End
2004-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Jurisic, Giorgia; Sundberg, John P; Detmar, Michael (2013) Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis 19:1983-9
Luckey, C John; Weaver, Casey T (2012) Stem-cell-like qualities of immune memory; CD4+ T cells join the party. Cell Stem Cell 10:107-8
Jurisic, G; Sundberg, J P; Bleich, A et al. (2010) Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease. Genes Immun 11:219-31
Bleich, Andre; B├╝chler, Gwen; Beckwith, Jason et al. (2010) Cdcs1 a major colitis susceptibility locus in mice; subcongenic analysis reveals genetic complexity. Inflamm Bowel Dis 16:765-75
Maynard, Craig L; Weaver, Casey T (2008) Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol Rev 226:219-33
Elson, Charles O; Cong, Yingzi; Weaver, Casey T et al. (2007) Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132:2359-70
Duverger, Alexandra; Jackson, Raymond J; van Ginkel, Frederick W et al. (2006) Bacillus anthracis edema toxin acts as an adjuvant for mucosal immune responses to nasally administered vaccine antigens. J Immunol 176:1776-83
Elson, Charles O; Cong, Yingzi; Qi, Fengxia et al. (2006) Molecular approaches to the role of the microbiota in inflammatory bowel disease. Ann N Y Acad Sci 1072:39-51
Konrad, Astrid; Cong, Yingzi; Duck, Wayne et al. (2006) Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology 130:2050-9
Lorenz, Robin G; McCracken, Vance J; Elson, Charles O (2005) Animal models of intestinal inflammation: ineffective communication between coalition members. Springer Semin Immunopathol 27:233-47

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