title: IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation.
abstract: SEE WINGER AND ZAMVIL DOI101093/BRAIN/AWW121 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood-brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation.
authors.affiliation: 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Cell Research and Immunology Department, Sagol School of Neuroscience, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 699788, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Mayo
authors.affiliation: 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Andre Pires Da
authors.initials: AP
authors.lastname: Cunha
authors.affiliation: 3 Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Asaf
authors.initials: A
authors.lastname: Madi
authors.affiliation: 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Beynon
authors.affiliation: 4 Environmental Health Department, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Yang
authors.affiliation: 5 Neuroimmunology Research Lab, CRCHUM, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada 6 Pathobiology Department, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: 5 Neuroimmunology Research Lab, CRCHUM, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: 7 Stanford University School of Medicine, Stanford, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: 4 Environmental Health Department, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.affiliation: 8 Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA hweiner@rics.bwh.harvard.edu.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016853:Muromonab-CD3 / Q000008:administration & dosage / Q000494:pharmacology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D007155:Immunologic Factors; D016853:Muromonab-CD3; D016753:Interleukin-10
keywords: T-lymphocytes; astrocyte; interleukin 10; multiple sclerosis; neuroinflammation