Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) induces tolerogenic dendritic cells that delay onset of type 1 diabetes by enhancing CD4+CD25+Foxp3+ regulatory T cells (50.33)

Abstract

Abstract Impairment in dendritic cell (DC) functions is implicated in defective immune regulation that leads to type-1 diabetes (T1D) in both humans and the established non-obese diabetic (NOD) mouse model. In this study, we examined the roles of DC modulators such as GM-CSF and Flt3-L to affect DC function and prevent T1D development in NOD mice. Both GM-CSF and FLT3-L could suppress the development of T1D if treatment was initiated earlier in life prior to the development of clinical diabetes. However, unlike Flt3-L, GM-CSF was far more effective in suppressing T1D even when administered at later stages of insulitis. Ongoing periodic treatment of NOD mice with GM-CSF prevented the development of T1D and the animals remained healthy until 3 months after cessation of the treatment. Adoptive transfer of CD4+CD25+ T cells from GM-CSF-treated mice could suppress effector T cell response and T1D in NOD-SCID mice, and this suppression was associated with enhanced IL-10 and TGF-β1 production. Moreover, adoptive transfer of GM-CSF-exposed DCs to naive NOD mice resulted in an expansion of Foxp3+ T cells and a significant delay in T1D onset. These results indicate that primarily the GM-CSF renders DCs tolerogenic resulting in subsequent Treg induction and delayed onset of T1D in NOD mice. NIH 1RO1AI058190