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J Immunol. 2014 Sep 1;193(5):2127-34. doi: 10.4049/jimmunol.1400857. Epub 2014 Jul 23.

Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis.

Author information

1
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
2
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
3
Department of Surgery, Cleveland Clinic, Cleveland, OH 44195;
4
Department of Hematology and Oncology, Case Western Reserve University, Cleveland, OH 44106;
5
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037; and.
6
Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037; and Department of Neurology, George Washington University, Washington, DC 20037.
7
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; linf2@ccf.org.

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.

PMID:
25057008
PMCID:
PMC4784709
DOI:
10.4049/jimmunol.1400857
[Indexed for MEDLINE]
Free PMC Article

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