Article

GM-CSF-induced regulatory T cells selectively inhibit anti-acetylcholine receptor-specific immune responses in experimental myasthenia gravis.

Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago, IL-60612, United States.
Journal of neuroimmunology (Impact Factor: 2.84). 11/2011; 240-241:65-73. DOI: 10.1016/j.jneuroim.2011.10.010
Source: PubMed

ABSTRACT We and others have demonstrated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to suppress autoimmunity by increasing the number of CD4(+)CD25(+) regulatory T cells (Tregs). In the current study, we have explored the critical role of induced antigen specific Tregs in the therapeutic effects of GM-CSF in murine experimental autoimmune myasthenia gravis (EAMG). Specifically, we show that Tregs from GM-CSF treated EAMG mice (GM-CSF/AChR-induced-Tregs) adoptively transferred into animals with EAMG suppressed clinical disease more potently than equal numbers of Tregs from either GM-CSF untreated EAMG mice or healthy mice treated with GM-CSF. In addition, GM-CSF/AChR-induced-Tregs selectively suppressed antigen specific T cell proliferation induced by AChR relative to that induced by an irrelevant self antigen, (thyroglobulin) and failed to significantly alter T cell proliferation in response to an exogenous antigen (ovalbumin). These results are consistent with the hypothesized mechanism of action of GM-CSF involving the mobilization of tolerogenic dendritic cell precursors which, upon antigen (AChR) capture, suppress the anti-AChR immune response through the induction/expansion of AChR-specific Tregs.

0 Bookmarks
 · 
123 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Guillain-Barré syndrome (GBS) is an acute inflammatory disease of the peripheral nervous system with considerable morbidity and mortality. EAN is an experimental model of GBS. EAN is caused by T cell-mediated inflammation. Aim: The purpose of this study was exploring the mechanisms underlying the beneficial effect of G-CSF in EAN. Results: Here, we demonstrate that the in vivo administration of G-CSF to Lewis rats with EAN led to a significant reduction of the proliferative response of autoreactive T lymphocytes with a concomitant decrease of the proinflammatory response and an increase of anti-inflammatory cytokines, such as IL-10, TGFβ and BDNF. Adoptive transfer of neuritogenic T lymphocytes cultured in the presence of G-CSF resulted in a less severe disease than that found in the control group. These results may be explained by the increase of Foxp3 expression in CD4+ and CD8+ T lymphocytes following treatment. Moreover, the increased expression of BDNF suggests that G-CSF acts simultaneously as an anti-inflammatory and a neuroprotective agent in EAN. Conclusion: Our data suggest that G-CSF acts simultaneously as an anti-inflammatory and a neuroprotective cytokine in the EAN model.
    CNS Neuroscience & Therapeutics 05/2013; · 4.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We recently demonstrated that hepatic stellate cells induce the differentiation of myeloid-derived suppressor cells (MDSCs) from myeloid progenitors. In this study, we found that adoptive transfer of these MDSCs effectively reversed disease progression in experimental autoimmune myasthenia gravis (EAMG), a T cell-dependent and B cell-mediated model for myasthenia gravis. In addition to ameliorated disease severity, MDSC-treated EAMG mice showed suppressed acetylcholine receptor (AChR)-specific T cell responses, decreased levels of serum anti-AChR IgGs, and reduced complement activation at the neuromuscular junctions. Incubating MDSCs with B cells activated by anti-IgM or anti-CD40 Abs inhibited the proliferation of these in vitro-activated B cells. Administering MDSCs into mice immunized with a T cell-independent Ag inhibited the Ag-specific Ab production in vivo. MDSCs directly inhibit B cells through multiple mechanisms, including PGE2, inducible NO synthase, and arginase. Interestingly, MDSC treatment in EAMG mice does not appear to significantly inhibit their immune response to a nonrelevant Ag, OVA. These results demonstrated that hepatic stellate cell-induced MDSCs concurrently suppress both T and B cell autoimmunity, leading to effective treatment of established EAMG, and that the MDSCs inhibit AChR-specific immune responses at least partially in an Ag-specific manner. These data suggest that MDSCs could be further developed as a novel approach to treating myasthenia gravis and, even more broadly, other diseases in which T and B cells are involved in pathogenesis.
    Journal of immunology (Baltimore, Md. : 1950). 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Autoimmune diseases arise from an inappropriate immune response against self components, including macromolecules, cells, tissues, organs etc. They are often triggered or accompanied by inflammation, during which the levels of granulocyte macrophage colony-stimulating factor (GM-CSF) are elevated. GM-CSF is an inflammatory cytokine that has profound impact on the differentiation of immune system cells of myeloid lineage, especially dendritic cells (DCs) that play critical roles in immune initiation and tolerance, and is involved in the pathogenesis of autoimmune diseases. Although GM-CSF was discovered decades ago, recent studies with some new findings have shed an interesting light on the old hematopoietic growth factor. In the inflammatory autoimmune diseases, GM-CSF redirects the normal developmental pathway of DCs, conditions their antigen presentation capacities and endows them with unique cytokine signatures to affect autoimmune responses. Here we review the latest advances in the field, with the aim of demonstrating the effects of GM-CSF on DCs and their influences on autoimmune diseases. The summarized knowledge will help to design DC-based strategies for the treatment of autoimmune diseases.
    Autoimmunity 06/2013; · 2.77 Impact Factor

Full-text (2 Sources)

View
7 Downloads
Available from
May 21, 2014