Ulcerative colitis and Crohn's disease, known as inflammatory bowel disease (IBD) are complex and poorly understood chronic inflammatory disorders of the intestine associated with and probably due to immune hyperreactivity to as yet known antigens. The disease pathogenesis appears to involve a complex interplay between genetics, the immune system, and the environment. T cells infiltrate the lesions in large number and are thought to be important in the pathogenesis. During the initial phase of this project we have demonstrated in two different models the ability of T cells to mediate colitis, as well as the presence of downregulatory processes that limit or prevent such T cell activity. Work elsewhere in which germ-free animals do not get experimental colitis, but those with a normal bacterial flora do, has implicated enteric bacteria as the source of the antigens driving chronic colonic inflammation. The working hypothesis of this project is that, although a number of initiating events may trigger acute colitis, progression to chronic colitis is due to a dysregulated immune response, particularly a T cell response, to antigens of the normal enteric bacterial flora. To address this question, we will utilize the newly developed G3H/HeJBir mouse strain, which spontaneously develops colitis with high frequency at the time of bacterial colonization and which have high-titer circulating antibodies to antigens of the enteric bacterial flora.
The Specific Aims of this project are to first test the hypothesis that there is a dysregulated mucosal immune response to enteric bacterial antigens in colitic G3H/HeJBir mice by determining the mechanism of increased intestinal S-lgA production, the site of origin and subclass (IgGl vs IgG2a) distribution of the IgG anti-bacterial response, the bacterial species of origin of the major enteric antigens recognized and whether healthy adult G3H/HeJBir mice have abnormally heightened anti-bacterial immune responses upon non-specific disruption of the colonic mucosal barrier. Second, isolate several of the major enteric bacterial antigens and develop monoclonal antibodies to determine the localization of these antigens in the colonic mucosa or draining lymph nodes during colitis by immunohistochemistry. Third, determine whether there is increased T cell recognition of enteric bacterial antigens in G3H/HeJBir mice using the T cell western blotting technique and what cytokines (Th1 vs Th2) are stimulated by the different antigen fractions. Fourth, test whether freshly isolated G3H/HeJBir T cells or bacterial- specific T cell lines or clones can induce colitis after adoptive transfer into immunodeficient G3H/HeJ SCID recipients. Fifth, determine the regulatory cells and cytokines that can down-regulate colitis in mice by co-transfer of potential regulatory cells along with disease-inducing T cells or by exogenous administration of inhibitory cytokines or cytokine inhibitors to the recipients. These studies will lead to new insights into the mechanism of chronic intestinal inflammation, as well as new paradigms, and possibly new therapies, to test in man.

Project Start
1998-09-01
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
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; Büchler, 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

Showing the most recent 10 out of 101 publications