The human class I major histocompatibility antigen HLA-B27 is strongly associated with a group of rheumatic disorders termed spondyloarthropathies. These disorders show a clinically well documented relationship to inflammatory bowel disease (IBD), although the basis for this relationship is not well understood. We have produced transgenic rats expressing HLA-B27, and have observed that they develop a multisystem disease that bears strong resemblance to the spectrum of disease encountered in humans with HLA-B27. The most striking aspect of this disease in the transgenic rats is chronic gastrointestinal inflammation, particularly in the colon but also involving the small intestine and stomach. This process shares a number of significant features with human IBD, and as a result, the B27 transgenic rats need to be considered as a potentially important animal model for IBD, understanding of which has been hampered in the past for lack of a faithful and convenient animal model. This project will examine the role of T lymphocytes in the pathogenesis of the inflammatory bowel disease of the B27 transgenic rats. Preliminary data indicates that T cells are critical for the initiation of the disease. These experiments, will be directed toward identifying the phenotype, ontogeny, and antigenic specificity of the disease-inducing T cells. The results should be specific information regarding the immune response leading to intestinal inflammation, and this would be expected to lead directly to a fundamentally improved understanding of the pathogenesis of IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047692-04
Application #
2016784
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1993-09-30
Project End
1998-08-31
Budget Start
1996-09-15
Budget End
1998-08-31
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Onderdonk, A B; Richardson, J A; Hammer, R E et al. (1998) Correlation of cecal microflora of HLA-B27 transgenic rats with inflammatory bowel disease. Infect Immun 66:6022-3
Simmons, W A; Summerfield, S G; Roopenian, D C et al. (1997) Novel HY peptide antigens presented by HLA-B27. J Immunol 159:2750-9
Simmons, W A; Roopenian, D C; Summerfield, S G et al. (1997) A new MHC locus that influences class I peptide presentation. Immunity 7:641-51
Breban, M; Fernandez-Sueiro, J L; Richardson, J A et al. (1996) T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats. J Immunol 156:794-803
Simmons, W A; Leong, L Y; Satumtira, N et al. (1996) Rat MHC-linked peptide transporter alleles strongly influence peptide binding by HLA-B27 but not B27-associated inflammatory disease. J Immunol 156:1661-7
Warner, T F; Madsen, J; Starling, J et al. (1996) Human HLA-B27 gene enhances susceptibility of rats to oral infection by Listeria monocytogenes. Am J Pathol 149:1737-43
Hammer, R E; Richardson, J A; Simmons, W A et al. (1995) High prevalence of colorectal cancer in HLA-B27 transgenic F344 rats with chronic inflammatory bowel disease. J Investig Med 43:262-8
Taurog, J D; Richardson, J A; Croft, J T et al. (1994) The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:2359-64