Autoimmunity in HLA-DQ8 transgenic mice expressing granulocyte/macrophage-colony stimulating factor in the beta cells of islets of langerhans

Abstract

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 Aß°.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. Aß°.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.

• Diabetes
• Autoimmunity
• HLA-DQ8
• GM-CSF
• Transgenic mice

Abbreviations
T1D	=	Type 1 diabetes
GM-CSF	=	granulocyte/macrophage colony-stimulating factor
NOD	=	Non-obese diabetic
MHC	=	Major histocompatibility complex
HLA	=	Human leukocyte antigen

Abbreviations
T1D	=	Type 1 diabetes
GM-CSF	=	granulocyte/macrophage colony-stimulating factor
NOD	=	Non-obese diabetic
MHC	=	Major histocompatibility complex
HLA	=	Human leukocyte antigen

Acknowledgements

We thank Julie Hanson and her crew for excellent mice husbandry, and Michelle Smart for characterizing the transgenic mice. We also acknowledge Lee Tucker (The Scripps Research Institute, La Jolla, CA) for providing the RIP.GM-CSF transgenic mice. Financial support from American Diabetes Association to CSD is also acknowledged. GR is a recipient of Juvenile Diabetes Research Foundation International fellowship award.