| First Author | Rajagopalan G | Year | 2003 |
| Journal | Int Immunol | Volume | 15 |
| Issue | 9 | Pages | 1035-44 |
| PubMed ID | 12917255 | Mgi Jnum | J:85223 |
| Mgi Id | MGI:2673101 | Doi | 10.1093/intimm/dxg103 |
| Citation | Rajagopalan G, et al. (2003) Autoimmune diabetes in HLA-DR3/DQ8 transgenic mice expressing the co-stimulatory molecule B7-1 in the beta cells of islets of Langerhans. Int Immunol 15(9):1035-44 |
| abstractText | 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 beta 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 (approximately 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 beta 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 beta 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. |
