Mouse Models for Celiac Disease

点击翻译按钮获取中文摘要

Celiac disease (cd) is a small intestinal inflammatory disorder that affects 1 out of 150 US citizens. It is triggered by consumption of gluten which is the storage protein of cereals. Treatment of cd is a strictly gluten-free diet. Screening- detected celiacs mostly have mild symptoms, but may develop a sudden exacerbation with diarrhoea and malabsorption, various autoimmune disorders or even malignancy as a consequence of remaining untreated. All celiac patients bear the HLA class II molecules DQ2 (or DQ8) and have serum antibodies directed to the ubiquitous self antigen tissue transglutaminase (tTG). CD4+ T helper 1 cells mediate most of the intestinal inflammation and the enzyme tTG potentiates the gluten-induced T cell activation. Our underlying hypotheses are that 1. the humoral and CD4+ T cell mediated autoimmunity to tTG plays an important role in the pathogenesis of cd, in particular of the associated autoimmune disorders and malignancies, 2. subpopulations ofgluten specific CD4+ Thelper 1 cells are instrumental in the inflammatory destruction of the intestinal villi of cd. Our goal is to study mouse models of adoptive T cell and immunoglobulin transfer that allow dissection of the immune processes that lead to cd and its complications. Aim#l focuses on the organ pathology after transfer of T cells and antibodies to tTG, generated in tTG-/- mice, intowildtype and T & B cell deficient mice. The profile and homing of pathogenic T cells will be analyzed, and the localization and role of autoantibodies dissected. Aim#2 will study the consequences of CD4+ T cells and the humoral immune response directed at gluten after intestinal repopulation with gluten-reactive mononuclear cells and subpopulations of CD4+ T cells in syngeneic T and B cell deficient recipients. Oral exposure to gluten and further challenge with indomethacin and/or cytokine modulation is expected to generate models that mimick human cd. Analysis of CD4+ T cell homingto the intestine, of CD4+ T cell subsets, and of the expected inflammatory and infiltrative lesions will be used to characterize the disease. The model of gluten-induced enteropathy will be developed as a translational tool to test non- dietary therapies for cd, such as 1. degradation of T cell stimulatory gliadin peptides by exogenous bacterial prolyl endopeptidases, 2. inhibition of intestinal tTG activity by tTG-inhibitors, and 3. downregulation of aggressiveintestinal T cells, e.g. by immunomodulatory cytokines or by cytokine antagonists. It is anticipated that the results will improve our understanding and management of cd and related autoimmune diseases.