Autoimmune diabetes in HLA-DR3/DQ8 transgenic mice expressing the co-stimulatory molecule B7-1 in the beta cells of islets of Langerhans.
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.
Rajagopalan
Govindarajan
G
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Kudva
Yogish C
YC
Chen
Lieping
L
Wen
Li
L
David
Chella S
CS
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006683:HLA-DQ Antigens / Q000235:genetics / Q000502:physiology*; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013311:Streptozocin / Q000008:administration & dosage / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D018122:B7-1 Antigen; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015803:HLA-DR3 Antigen; D013311:Streptozocin