Autoimmune diabetes in HLA-DR3/DQ8 transgenic mice expressing the co-stimulatory molecule B7-1 in the cells of islets of Langerhans

Abstract

The major predisposing genetic component in type 1 diabetes (T1D) maps to the MHC locus in both mice and humans. To better understand the HLA class II association with disease pathogenesis, we bred mice expressing HLA‐DQ8 and ‐DR3, either alone or in combination, to transgenic mice expressing the co‐stimulatory molecule B7‐1 in the β cells of islets of Langerhans. Spontaneous diabetes occurred only in RIP‐B7‐1 transgenic mice expressing transgenic HLA‐DR3 or ‐DQ8 molecules and the incidence of diabetes was comparable between the two (∼30% in either sex up to 50 weeks of age). Presence of DR3 and DQ8 together only marginally elevated the overall incidence of spontaneous disease (38%). Non‐specific activation of T cells by superantigen and provision of concomitant co‐stimulation through 4‐1BB (CD137) by an agonistic antibody did not accelerate the incidence of diabetes over a short period of time. Neither the antibody‐mediated depletion of CD25⁺ T cells nor sublethal, whole‐body irradiation of young, naive HLA transgenic mice expressing RIP‐B7‐1 resulted in diabetes. However, administration of only two doses of the β cell toxin streptozotocin (STZ; 40 mg/kg) induced autoimmune diabetes in 85% of mice within 7 weeks after STZ treatment only when B7‐1 was expressed on the pancreatic β cells. This effect was HLA dependent as none of the STZ‐treated RIP‐B7‐1 transgenic mice lacking HLA class II developed diabetes. In conclusion, this study confirmed the diabetogenic potential of HLA‐DQ8 and established the role of HLA‐DR3 in the pathogenesis of T1D.