Suppression of Experimental Autoimmune Myasthenia Gravis by Granulocyte-Macrophage Colony-Stimulating Factor Is Associated with an Expansion of FoxP3+ Regulatory T Cells

Abstract

Dendritic cells (DCs) have the potential to activate or tolerize T cells in an Ag-specific manner. Although the precise mechanism that determines whether DCs exhibit tolerogenic or immunogenic functions has not been precisely elucidated, growing evidence suggests that DC function is largely dependent on differentiation status, which can be manipulated using various growth factors. In this study, we investigated the effects of mobilization of specific DC subsets—using GM-CSF and fms-like tyrosine kinase receptor 3-ligand (Flt3-L)—on the susceptibility to induction of experimental autoimmune myasthenia gravis (EAMG). We administered GM-CSF or Flt3-L to C57BL/6 mice before immunization with acetylcholine receptor (AChR) and observed the effect on the frequency and severity of EAMG development. Compared with AChR-immunized controls, mice treated with Flt3-L before immunization developed EAMG at an accelerated pace initially, but disease frequency and severity was comparable at the end of the observation period. In contrast, GM-CSF administered before immunization exerted a sustained suppressive effect against the induction of EAMG. This suppression was associated with lowered serum autoantibody levels, reduced T cell proliferative responses to AChR, and an expansion in the population of FoxP3+ regulatory T cells. These results highlight the potential of manipulating DCs to expand regulatory T cells for the control of autoimmune diseases such as MG.

Granulocyte-Macrophage Colony-Stimulating Factor Prevents Diabetes Development in NOD Mice by Inducing Tolerogenic Dendritic Cells that Sustain the Suppressive Function of CD4+CD25+ Regulatory T Cells

“…We showed in this study that GM-CSF, a cytokine that has been previously shown to increase the number of DCs and CD4 ϩ CD25 ϩ Tregs in vivo (12,13,31), provided significant protection against the development of diabetes in NOD mice. Our data provided the first evidence that such a protective effect was dependent on expanded DCs acquiring semimature phenotype under maturation stimuli.…”

A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

“…Alternatively, some regulatory mechanism against hCOL17-specific T cells, B cells, or both may be induced in this BP model. In experimental autoimmune myasthenia gravis, an autoimmune neuromuscular disease model induced by anti-acetylcholine receptor Abs, regulatory T cells (Tregs) generated ex vivo or expanded in vivo suppress pathogenic T cell and Ab responses (29,30). In experimental autoimmune encephalomyelitis, a myelin-reactive T cell-dependent multiple sclerosis model, natural resolution correlates with the accumulation of myelin-reactive Tregs expanded during the course of experimental autoimmune encephalomyelitis in the inflamed CNS (31,32 (33,34).…”

Cells with regulatory function of the innate and adaptive immune system in primary Sjögren’s syndrome

“…+ T cells in the thymus were found to produce decreased levels of FoxP3, indicating damaged cell function [21,22]. Additionally, in the peripheral blood of these patients, fewer CD4 +…”