title: Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis.
abstract: Mesenchymal stem cells (MSCs) possess immunomodulatory properties and have potential, however, there have been conflicting reports regarding their effects in rheumatoid arthritis (RA), which causes inflammation and destruction of the joints. Through a comparative analysis of regulatory T (Treg) and IL-10-producing type 1 regulatory T (Tr1) cells, we hypothesized that Tr1 cells enhance the immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy may exert synergistic immunomodulatory effects in an experimental animal model of rheumatoid arthritis (RA). A combination of MSCs and Tr1 cells prevented the development of destructive arthritis compared to single cell therapy. These therapeutic effects were associated with an increase in type II collagen (CII)-specific CD4+CD25+Foxp3+ Treg cells and inhibition of CII-specific CD4+IL-17+ T cells. We observed that Tr1 cells produce high levels of IL-10-dependent interferon (IFN)-β, which induces toll-like receptor (TLR) 3 expression in MSCs. Moreover, induction of indoleamine 2,3-dioxygenase (IDO) by TLR3 involved an autocrine IFN-β that was dependent on STAT1 signaling. Furthermore, we observed that production of IFN-β and IL-10 in Tr1 cells synergistically induces IDO in MSCs through the STAT1 pathway. These findings suggest co-administration of MSCs and Tr1 cells to be a novel therapeutic modality for clinical autoimmune diseases.
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Jung-Yeon
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Keon-Il
authors.initials: KI
authors.lastname: Im
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Eun-Sol
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Nayoun
authors.initials: N
authors.lastname: Kim
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Nam
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Jeon
authors.affiliation: Institute for Translational Research and Molecular Imaging, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.|Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Seok-Goo
authors.initials: SG
authors.lastname: Cho
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D004790:Enzyme Induction; D005786:Gene Expression Regulation / Q000276:immunology; D056747:Immunomodulation; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D050794:STAT1 Transcription Factor / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C556062:IL10 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D016753:Interleukin-10; D016899:Interferon-beta