title: Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis.
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.
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors: Yan
authors: Y
authors: Li
authors: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
authors: Zhidan
authors: Z
authors: Tu
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors: Shiguang
authors: S
authors: Qian
authors: Department of Surgery, Cleveland Clinic, Cleveland, OH 44195;
authors: John J
authors: JJ
authors: Fung
authors: Department of Hematology and Oncology, Case Western Reserve University, Cleveland, OH 44106;
authors: Sanford D
authors: SD
authors: Markowitz
authors: Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037; and.
authors: Linda L
authors: LL
authors: Kusner
authors: Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037; and Department of Neurology, George Washington University, Washington, DC 20037.
authors: Henry J
authors: HJ
authors: Kaminski
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors: Lina
authors: L
authors: Lu
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; linf2@ccf.org.
authors: Feng
authors: F
authors: Lin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015232:Dinoprostone / Q000276:immunology; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D011978:Receptors, Nicotinic / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011978:Receptors, Nicotinic; D015232:Dinoprostone