Perméabilité intestinale: un facteur clé de l'intolérance au gluten – GLUTEN

The prevalence of gluten intolerance (or celiac disease, CD) is in progression like many other allergic and auto-immune diseases. This food intolerance to wheat proteins and to other cereal proteins is characterized by abnormal immune responses to gluten, associated with auto-immunity to tissue transglutaminase, intestinal villus atrophy and generalized malabsorption. Up to now, the only treatment available is a strict gluten-free diet, extremely restrictive, and new therapeutic options are highly expected. In this project, we are interested in the first step involved in the pathological process , namely the entry of gliadin peptides in the intestinal mucosa. Indeed, we recently reported the importance of such step in the pathogenesis of the disease (Matysiak-Budnik et al J Exp Med 2008, Schumann M et al, Gut 2008). The present work is aimed at a better understanding of the mechanisms involved in the entry of gliadin peptides at the epithelial level, in order to define new therapeutic targets of the disease. Two research teams will participate , both of them have a good experience in intestinal permeability in various digestive pathologies (JD Schulzke, Germany and M. Heyman, France). Efforts will be directed to set up a murine model of CD, based on the recent finding of the implication of CD71 (transferrin receptor but also IgA1 receptor) in the "protected" intestinal transport of IgA/gliadin complexes. IL-15 as well as HLA-DQ2 transgenic mice will be used to study molecular mechanisms and identify new therapeutic targets. In such model(s), the respective role of transcellular versus paracellular epithelial transport pathways will be studied, as this step is mandatory to identify relevant epithelial targets in view of attenuating gliadin absorption. The project will consist in a) setting up a murine model of CD, in IL-15 and/or HLA-DQ2 mice, by promoting the overexpression of intestinal IgA receptor, CD71, in mice fed iron-deficient diet, b) studying pathways of intestinal transport of p31-49 and 33-mer gliadin peptides in this murine model (Transport in Ussing chambers, confocal microscopy on fixed tissue sections or by live imaging, immunofluorescence) and in intestinal epithelial cell lines (CaCO2, HT29-19A). The achievement of such goals and the characterization of transport pathways (transcellular versus paracellular) will allow define targets to inhibit, in order to dampen gluten entry and abnormal immune response in CD,