(taken from application) Genetic and environmental factors are extremely important in the pathogenesis of the idiopathic chronic inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD). New rodent models of chronic intestinal inflammation have contributed substantially to our knowledge of the pathogenesis of IBD. One better characterized model is HLA-B27 transgenic rats, in which the overexpression of the gene for the MHC class I molecule HLA-B27 leads to the spontaneous development of colitis, gastroduodenitis, peripheral arthritis and spondylitis. Our hypothesis is that chronic colitis and gastritis is the result of an overly aggressive immune response to luminal bacteria in a genetically susceptible host. This T Iymphocyte-dominated immune response to specific luminal bacteria is regulated by antigen presenting cells (APC). This hypothesis will be evaluated in HLA-B27 transgenic rats, which develop progressive colitis, gastritis and arthritis when raised in specific pathogen-free environment or when colonized with Bacteroides vulgatus, but which have no clinical or histological disease when raised in a sterile environment or monoassociated with E. coli. However, the immunological mechanisms determining how these bacteria initiate and perpetuate a chronic immune response need to elucidated. The unraveling of these mechanisms will answer several fundamental questions concerning the pathogenesis of chronic inflammatory bowel diseases. We will address several fundamental questions of IBD pathogenesis in the following specific aims: 1) Determine which bacterial components induce gastrointestinal inflammation and conversely, whether certain resident luminal bacteria can prevent this inflammation. 2) Define the mechanisms by which T lymphocytes induce or prevent gastrointestinal inflammation. Successful completion of these specific aims will not only provide essential insights into the pathogenesis of experimental intestinal inflammation, but will also reveal pathogenetic mechanisms of IBD and suggest novel therapeutic approaches targeting etiologic mechanisms. This MD/PhD has considerable experience with various studies on the role of cytokines in several murine models of acute and chronic intestinal inflammation. The research project for this grant will enable the candidate to expand his knowledge in new areas of cellular immunology and gnotobiotic technology, which will be complemented by formal immunology/microbiology courses. This training experience will take place in a Digestive Disease Center focused on inflammation and fibrosis under the sponsorship of experts in animal studies, gnotobiotic research and cellular immunology. This expertise will foster the development of an independent investigator with skills in both clinical and basic science.
| Hoentjen, Frank; Tonkonogy, Susan L; Qian, Bi-Feng et al. (2007) CD4(+) T lymphocytes mediate colitis in HLA-B27 transgenic rats monoassociated with nonpathogenic Bacteroides vulgatus. Inflamm Bowel Dis 13:317-24 |
| Hoentjen, F; Tonkonogy, S L; Liu, B et al. (2006) Adoptive transfer of nontransgenic mesenteric lymph node cells induces colitis in athymic HLA-B27 transgenic nude rats. Clin Exp Immunol 143:474-83 |
| Dieleman, L A; Hoentjen, F; Qian, B-F et al. (2004) Reduced ratio of protective versus proinflammatory cytokine responses to commensal bacteria in HLA-B27 transgenic rats. Clin Exp Immunol 136:30-9 |
