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 1 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 lymphocyte-dominated immune response to specific luminal bacteria is regulated by antigen presenting cells (APC). This hypothesis is 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. In the first 2 years of the K08 award (DK 02551) we studied the role of inducing and protective intestinal organisms in our model. In specific-pathogen-free conditions (SPF) we found that oral broad spectrum antibiotics can prevent and treat established colitis in SPF B27 TG rats, which will recur after the treatment is stopped. Lactobacillus casei GG (L.GG) can prevent the disease recurrence after treatment with antibiotics. However, the immunological mechanisms determining how these bacteria prevent a chronic immune response need to be elucidated. In this R03 application we will address the following specific aims: 1. Determine in-vivo immune mechanisms by which Lactobacillus GG can prevent relapse of colitis in SPF HLA-B27 TG rats treated with antibiotics. 2. Investigate if protective immune responses are mediated by L.GG-specific inhibitory T lymphocytes.
| Hoentjen, Frank; Welling, Gjalt W; Harmsen, Hermie J M et al. (2005) Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis 11:977-85 |
