Co-expression of HLA DR3 and DQ8 results in the development of spontaneousinsulitis and loss of tolerance to GAD65 in transgenic mice

Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in Linkage disequilibrium with at-risk DR4 and DR3 allele s, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the great est risk. A double transgenic mouse expressing both DR3 and DQ8 was generat ed to investigate potential major histocompatibility complex class II inter actions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolera nce to GAD65, in which the T-cell response to GAD65 was restricted by HLA D R. Although the mice also showed spontaneous insulitis, they did not progre ss to overt diabetes, Mice expressing either transgene (DQ8 or DR3) alone s howed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. The refore, in a fashion analogous to human diabetes, the murine model demonstr ated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.