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

Abstract

Celiac disease is a chronic inflammatory disorder of the small intestine with a strong association to HLA-DQ2. This thesis focused on peptide binding to HLA-DQ2 and the development of peptide blockers for the treatment of celiac disease. We have investigated the relative contribution of each hydrogen bond interaction between the peptide main chain and MHC residues in DQ2 and our results demonstrated that hydrogen bonds at positions P4 and P2 are most important for peptide binding. In addition, no evidence of a hydrogen bond in position P1 was found. Detailed characterization of gluten T cell epitopes gave knowledge on the importance of proline spacing for the binding to DQ2. Cyclic and dimeric peptides were investigated as peptide blockers, and we demonstrated proof-of principle for inhibition of DQ2 mediated presentation of gluten T cell epitopes. Finally, a study was performed to elucidate peptide determinant selection by HLA-DQ2 as a factor to explain the strong HLA association in celiac disease. The results demonstrated that the gluten T cell epitopes mainly bind to HLA-DQ2 and not to other HLA class II molecules.