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: 2.47). 11/2011; 240-241:65-73. DOI: 10.1016/j.jneuroim.2011.10.010
Source: PubMed


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.

Download full-text


Available from: Bellur S Prabhakar, Feb 25, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: New treatments for immune mediated diseases have increased notably in the last 10 years. Monoclonal antibodies directed against different components of the immune system have appeared, along with new drugs from the haematology field. In the case of myasthenia gravis (MG), many of these new treatments have been used in experimental animal models and also in patients. Areas covered: This manuscript reviews the progress in the field of MG treatment achieved in the last 5 years. Firstly, our current treatment protocol is introduced. Secondly, new data from recent randomized trials and case series of patients treated with methotrexate, cyclophosphamide, rituximab or improved systems of apheresis is reported. Finally, all future treatments are discussed that are currently under evaluation in preclinical animal models of experimental autoimmune MG. Expert opinion: Evidence supporting the use of methotrexate and rituximab in MG has been published recently, in addition to conflicting randomized trials that were not successful, evaluating the use of tacrolimus as a steroid sparing agent. New promising treatments are currently under evaluation in clinical trials, such as belimumab and eculizumab.
    Expert Opinion on Pharmacotherapy 07/2012; 13(13):1873-83. DOI:10.1517/14656566.2012.705831 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies have reported alterations in numbers or function of regulatory T (Treg) cells in myasthenia gravis (MG) patients, but published results have been inconsistent, likely due to the isolation of heterogenous "Treg" populations. In this study, we used surface CD4, CD25(high), and CD127(low/-) expression to isolate a relatively pure population of Tregs, and established that there was no alteration in the relative numbers of Tregs within the peripheral T cell pool in MG patients. In vitro proliferation assays, however, demonstrated that Treg-mediated suppression of responder T (Tresp) cells was impaired in MG patients and was associated with a reduced expression of FOXP3 in isolated Tregs. Suppression of both polyclonal and AChR-activated Tresp cells from MG patients could be restored using Tregs isolated from healthy controls, indicating that the defect in immune regulation in MG is primarily localized to isolated Treg cells, and revealing a potential novel therapeutic target.
    Clinical Immunology 10/2012; 145(3):209-223. DOI:10.1016/j.clim.2012.09.012 · 3.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Forkhead box P3 (FOXP3) is a transcription factor necessary for the function of regulatory T cells (T(reg) cells). T(reg) cells maintain immune homeostasis and self-tolerance and play an important role in the prevention of autoimmune disease. Here, we discuss the role of T(reg) cells in the pathogenesis of myasthenia gravis (MG) and review evidence indicating that a significant defect in T(reg) cell in vitro suppressive function exists in MG patients, without an alteration in circulating frequency. This functional defect is associated with a reduced expression of key functional molecules, such as FOXP3 on isolated T(reg) cells, and appears to be more pronounced in immunosuppression-naive MG patients. In vitro administration of granulocyte macrophage-colony-stimulating factor (GM-CSF) enhanced the suppressive function of T(reg) cells and upregulated FOXP3 expression. These findings indicate a clinically relevant T(reg) cell-intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target.
    Annals of the New York Academy of Sciences 12/2012; 1274(1):68-76. DOI:10.1111/j.1749-6632.2012.06840.x · 4.38 Impact Factor
Show more