DO GUT BACTERIA PROVOKE INFLAMMATORY BOWEL DISEASE?

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DESCRIPTION The two research groups [Dr. John Cebra, Professor of Biology, University of Pennsylvania, Philadelphia, and Dr. Helena Tlaskalova et. al., Institute of Microbiology, Prague, Czech Republic], under the auspices of the Fogarty Award [FIRCA], plan to analyze a number of murine models for human inflammatory bowel disease [IBD]. Their aim is to assess whether and which gut bacteria or food antigens [Ags] may act to provoke or exacerbate inflammatory bowel lesions by stimulating one or more elements of the mucosal immune system. They will further examine how deviation of the normal gut mucosal response against "normal" intestinal antigens may result from dysregulation of the overall immune system and whether it can lead to frank autoimmunity. The Pennsylvania group has been elucidating the details of the 'normal' humoral and cellular mucosal immune responses to commensal gut bacteria --how these responses lead to the development of the 'normal' physiologic state of the gut system and are normally self-limiting. The Czeck group has been assessing how oral feeding with gliadin [wheat protein] can induce intestinal lesions in a number of murine models -- apparently due to dysregulation of the 'normal' immune response. The Czech group has established colonies of germ free [GF] IL-2 (-/-) mice and GF severe-combined-immunodeficient [SCID] mice. These, and athymic (nu/nu) murine models for IBD will be used to test the role(s) of normal commensal bacteria, opportunistic pathogens, and food antigens as provocateurs of intestinal bowel lesions, using cellular and molecular techniques. Adoptive transfers of sub-sets of mucosal cellular elements will be used to reveal the role(s) and possible antigen specificities of provocateurs or regulatory cells in Intestinal Bowel Disease. Immunohistochemical analyses will be used to identify the elements involved in pathogenic processes in situ. In vitro assays of elements of the mucosal system: Peyer's patch [PP] or lamina propria [LP] B cells, NK and CD8+ T cells in the intra epithelial leukocyte [IEL] space, and CD4+ T cells in peyer's patch and lamina propria reactive against gut microbial and foods antigens will also be used. Gram negative [E. Coli, M. morganii, bacteroides, S. Typhimurium-avirulent], Gram positive [lactobacillus, enterococcus, L. monoctogenes-avirulent, segmented filamentous bacteria], and wheat gliadin will be tested as possible provocateurs.