Peptide binding to HLA-DQ2 and development of blocking agents for the treatment of celiac disease

Celiac disease is a prevalent disease affecting about 1:100 Scandinavians. The only treatment available today is lifelong exclusion of gluten from the diet. This is a cumbersome treatment and the patients are asking for alternative treatments. Celiac dise ase develops as the result of an inappropriate T cell mediated immune response against ingested gluten in genetically predisposed people. HLA is the single most important gentic factor; HLA-DQ2 is involved in the majority and HLA-DQ8 is involved in the mi nority of the patients. Expression of these HLA molecules is necessary but not sufficient for disease development. The HLA molecules are involved in the disease pathogenesis by presenting gluten peptides to CD4+ T cells. On recognition of gluten/HLA compl exes the T cells become activated and initiate an immunological cascade finally leading to celiac disease. Blocking the peptide-binding sites of these HLA molecules is thus an attractive target for therapy. A compound that blocks the binding site of an HL A molecule should retain the ability to bind tightly to the HLA molecule, be proteolytically stable and be unable to elicit T cell responses by itself. The alphaI T cell epitope, is a gluten T cell epitope recognized by celiac disease T cells when bound t o HLA-DQ2. We utilize information from the X-ray crystal structure of the alphaI-DQ2 complex to design peptide blockers for HLA-DQ2. Peptide blockers will be synthesized at Stanford University and tested for biological effect in various assays at the Univ ersity of Oslo. The aim of the project is to provide proof of principle of this therapeutic concept. The results of the project will be highly relevant for the development of similar compounds for the treatment of other HLA associated diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis.