title: Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs.
abstract: Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25- T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-beta-dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lüth
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.forename: Thorsten
authors.initials: T
authors.lastname: Buch
authors.forename: Stefan
authors.initials: S
authors.lastname: Zander
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001921:Brain / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D009474:Neurons / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D013997:Time Factors
chemical_list: D001324:Autoantigens; D004676:Myelin Basic Protein