Most DR4+ Caucasian patients with IDDM have the DQB1*0302 gene, however most individuals with this gene do not have diabetes. It is proposed that the DQw3.2 molecule acts as a peptide binding molecule to trigger T cell activation which leads to destruction of beta cells in the pancreatic islet. In order to better understand this pathogenesis mechanism, detailed studies of the trimolecular interaction between the DQ/peptide and T cell receptor are essential. Our previous R29 grant focused on the structural determinants of the DQw3.2 molecule. As an extension of the previous studies, this proposal is focused on the interaction between DQ molecules and DQ binding peptides. An in vivo binding assay will be established to examine the effect of DQ-alpha and DQ-beta polymorphisms on DQ/peptide interactions. An M13 phage peptide binding assay will also be used to identify the binding motif of DQ binding peptides. This binding motif will be used to predict DQ- restricted T cell epitopes of potential diabetogenic autoantigens. T cells that recognize this DQ/peptide complex will be generated and characterized. These studies address an important and poorly understood area of immunogenetics and diabetes -- namely, the specific nature of peptides which are preferentially bound to DQ molecules associated with disease. This information is essential for the rational design of immunotherapeutics directed at the trimolecular complex in IDDM.
| Buckner, J; Kwok, W W; Nepom, B et al. (1996) Modulation of HLA-DQ binding properties by differences in class II dimer stability and pH-dependent peptide interactions. J Immunol 157:4940-5 |
