An estimated 3-7% of Europe's population (80% females) suffer from autoimmune diseases (AID) that affect the body's various organs. In healthy people, harmless proteins from self, bacterial flora or food do not elicit a destructive inflammatory response due to antigen tolerance. Central to antigen tolerance is the function of regulatory T cells, a population of lymphocytes key to the prevention of excessive inflammatory tissue damage by immune effector cells. Unfortunately, the mechanisms that safeguard a balanced interaction of HLA class II-restricted regulatory and effector CD4+ T cells are incompletely understood. This explains why the current treatment of AID remains inadequate. Towards the priority research areas for chronic inflammatory diseases identified in the Innovative Medicines Initiative's Research Agenda 2008, we suggest the following original approaches: 1.) Identification of the functional roles of HLA class II-restricted CD4+ T cells in the induction/prevention of AID using a HLA-DR*0405 transgenic mouse model of autoimmune pancreatitis (AIP); 2.) identification of humoral autoantigens that can aid in the diagnosis of AIP; 3.) enhancement of a novel mouse model of human celiac disease (CD) by introduction of the CD-associated HLA-DQ8 (class II) allele; and 4.) pre-clinical testing of oral enzyme therapy, currently the most promising alternative treatment approach to CD, comparing efficacy in the existing CD mouse model of a 2-enzyme-glutenase (prolyl endopeptidase and endoprotease B2) vs. an extract of germinating wheat enzymes. This project will lead to insight into pathomechanisms that underlie loss of antigen tolerance in HLA-associated AID, development of a diagnostic serum test for AIP, analysis of the HLA-dependency of CD-specific autoantibodies and proof-of-efficacy in vivo for oral enzyme therapy of CD.