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 receptors (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 antibodies inhibited the proliferation of these in vitro activated B cells. Administering MDSCs into mice immunized with a T-cell-independent antigen inhibited the antigen-specific antibody production in vivo. MDSCs directly inhibit B cells through multiple mechanisms including prostaglandin E2, inducible nitric oxide synthase and arginase. Interestingly, MDSC treatment in EMAG mice does not appear to significantly inhibit their immune response to a non-relevant antigen, ovalbumin. 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 antigen-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.

Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death–Ligand 1

“…Although in mice, tail vein i.v. injection has been successfully employed to systemically deliver many cell types (e.g., dendritic cells43, myeloid-derived suppressor cells44, and mesenchymal stem cells45), we found that tail vein i.v. injection of primary HSCs led to lethal pulmonary embolisms, potentially due to the large size of HSCs, which made our in vivo studies to test the effect of HSCs in inhibiting B-cell responses impossible.…”

GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells

“…MDSCs can be generated from normal BM in a relatively short amount of time and have been shown to effectively suppress GVHD 8,23 as well as autoimmunity 24 and allograft rejection. 25,26 In our studies, we have found that MDSCs activated by the cytokine IL-13 produce Arg1 that is in turn critical to their ability to suppress GVHD.…”

In vitro-generated MDSCs prevent murine GVHD by inducing type 2 T cells without disabling antitumor cytotoxicity

“…[10][11][12][13][14] MDSCs can be generated in vitro by various methods using different progenitor cells and cytokine combinations for differentiation and expansion. [15][16][17][18][19] Usage of MDSCs as cellular therapy was effective for inhibition of experimental autoimmune myasthenia gravis, 18 prolonging allograft survival, 20 and for GVHD prevention, 16,17 clearly indicating that these cells have a therapeutic potential in T-cell-mediated diseases.…”