Accelerated diabetes in rat insulin promoter-tumor necrosis factor-alpha transgenic nonobese diabetic mice lacking major histocompatibility class II molecules.
The major predisposing genetic component in type 1 diabetes maps to the major histocompatibility complex locus in both mice and humans. To verify the HLA class II association with disease pathogenesis, we adopted the transgenic approach. Expression of HLA-DQ8, the molecule showing the strongest association with human type 1 diabetes, in the diabetes-predisposing milieu of NOD mice in the absence of the endogenous class II molecule I-A(g7) did not render susceptibility to type 1 diabetes. To study if providing a local proinflammatory environment would lead to diabetes in these mice, Abeta(o).NOD.DQ8 were bred with C57BL/6 mice expressing tumor necrosis factor (TNF)-alpha in the beta-cells of the islets of Langerhans. Surprisingly, although diabetes was evident in the F1 intercross expressing rat insulin promoter (RIP)-TNF, offspring lacking either endogenous or transgenic class II molecules developed accelerated diabetes with high frequency in both sexes. Moreover, expression of any functional class II molecule seemed to confer significant protection from diabetes in this model. Thus, neonatal expression of TNF-alpha in an islet-specific manner bypassed the requirement of CD4(+) T-cells and resulted in diabetes that could be mediated by CD8(+) T-cells. We also show for the first time that diabetes in NOD.RIP-TNF mice can occur independent of inheritance of NOD-derived idd1.
Rajagopalan
Govindarajan
G
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Kudva
Yogish C
YC
Flavell
Richard A
RA
David
Chella S
CS
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D015994:Incidence; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D051381:Rats; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000949:Histocompatibility Antigens Class II; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha