Characterization of HLA-DQ8alpha/DQ2beta transgenic IAbeta null NOD mice as a model for type 1 diabetes

Susceptibility to type 1 diabetes in humans is strongly associated with the heterozygous MHC class II haplotype DQ8/DQ2 (DQA1*301/B1*302, DQA1*0501/B1*0201). It has been hypothesized that the formation of DQ8alpha/DQ2beta trans-heterodimers unique to these heterozygous individuals is responsible for the high risk associated with this haplotype. A DQ8alpha/DQ2beta transgenic IAbeta null NOD mouse line was established and this thesis describes the characterization of these mice as a potential humanized model for type 1 diabetes. The DQ transgenic mice developed severe insulitis and a small percentage progressed to diabetes. Since the DQ8alpha/DQ2beta molecule is the only MHC class II restriction element present in these mice, they provide a useful model to examine responses to diabetes autoantigens and to map epitopes restricted to the DQ8alpha/DQ2beta trans-heterodimer. By immunizing the mice with whole antigens and examining recall responses to overlapping sets of peptides, T cell epitopes were mapped for human proinsulin, IA-2 and GAD65. These mice provide a useful tool to gain further insights into the contribution of the DQ8alpha/DQ2beta trans-heterodimer to diabetes autoimmunity in humans.