title: Suppression of proteoglycan-induced autoimmune arthritis by myeloid-derived suppressor cells generated in vitro from murine bone marrow.
abstract: BACKGROUND
  Myeloid-derived suppressor cells (MDSCs) are innate immune cells capable of suppressing T-cell responses. We previously reported the presence of MDSCs with a granulocytic phenotype in the synovial fluid (SF) of mice with proteoglycan (PG)-induced arthritis (PGIA), a T cell-dependent autoimmune model of rheumatoid arthritis (RA). However, the limited amount of SF-MDSCs precluded investigations into their therapeutic potential. The goals of this study were to develop an in vitro method for generating MDSCs similar to those found in SF and to reveal the therapeutic effect of such cells in PGIA.
  
  
  METHODS
  Murine bone marrow (BM) cells were cultured for 3 days in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF). The phenotype of cultured cells was analyzed using flow cytometry, microscopy, and biochemical methods. The suppressor activity of BM-MDSCs was tested upon co-culture with activated T cells. To investigate the therapeutic potential of BM-MDSCs, the cells were injected into SCID mice at the early stage of adoptively transferred PGIA, and their effects on the clinical course of arthritis and PG-specific immune responses were determined.
  
  
  RESULTS
  BM cells cultured in the presence of GM-CSF, IL-6, and G-CSF became enriched in MDSC-like cells that showed greater phenotypic heterogeneity than MDSCs present in SF. BM-MDSCs profoundly inhibited both antigen-specific and polyclonal T-cell proliferation primarily via production of nitric oxide. Injection of BM-MDSCs into mice with PGIA ameliorated arthritis and reduced PG-specific T-cell responses and serum antibody levels.
  
  
  CONCLUSIONS
  Our in vitro enrichment strategy provides a SF-like, but controlled microenvironment for converting BM myeloid precursors into MDSCs that potently suppress both T-cell responses and the progression of arthritis in a mouse model of RA. Our results also suggest that enrichment of BM in MDSCs could improve the therapeutic efficacy of BM transplantation in RA.
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America; Department of Rheumatology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary.
authors.forename: Júlia
authors.initials: J
authors.lastname: Kurkó
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: András
authors.initials: A
authors.lastname: Vida
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Tímea
authors.initials: T
authors.lastname: Ocskó
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Beata
authors.initials: B
authors.lastname: Tryniszewska
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Tibor A
authors.initials: TA
authors.lastname: Rauch
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.affiliation: Department of Rheumatology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szekanecz
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D001854:Bone Marrow Cells / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D022423:Myeloid Cells / Q000637:transplantation*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009928:Organ Specificity; D011509:Proteoglycans
chemical_list: D011509:Proteoglycans; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse