Type 1 diabetes (T1D) is a polygenic autoimmune disease with a strong HLA association particularly, HLA-DQ8. We investigated whether islet-specific expression of granulocyte/macrophage colony-stimulating factor (Ins.GM-CSF) in A Beta degrees.NOD.DQ8 mice (HLA-DQ8 transgenic mice on a NOD background lacking endogenous mouse MHC class II molecules) would predispose to development of spontaneous autoimmune diabetes. A Beta degrees.NOD.DQ8 mice expressing GM-CSF in the pancreatic ss cells (8+ G+) as well as litter mates lacking either HLA-DQ8 (8 - G+) or GM-CSF (8+ G -) or both (8 - G -) exhibited insulitis and sialadenitis of varying degrees. But none of the mice progressed to develop T1D. Other than the marked mononuclear cell infiltration in livers of mice expressing GM-CSF irrespective of HLA-DQ8 expression (8+ G+ or 8 - G+), no other changes were observed in the animals. Thus, we have shown for the first time that expression of HLA-DQ8 in the diabetes-predisposing mileu of NOD genetic background is not sufficient to predispose to development of autoimmune diabetes even when the potent immunostimulatory cytokine, GM-CSF is expressed in the pancreatic islets.