| Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. | |
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MedLine Citation:
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PMID: 20332205 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25(+)Foxp3(+) regulatory T (T(reg)) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-gamma and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T(reg) cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis. |
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Authors:
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Mahdia Benkhoucha; Marie-Laure Santiago-Raber; Gregory Schneiter; Michel Chofflon; Hiroshi Funakoshi; Toshikazu Nakamura; Patrice H Lalive |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-23 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-07 Completed Date: 2010-05-05 Revised Date: 2010-10-07 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 6424-9 Citation Subset: IM |
Affiliation:
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Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigen Presentation Cell Proliferation Cytokines / biosynthesis, immunology Dendritic Cells / immunology* Encephalomyelitis, Autoimmune, Experimental / genetics, immunology* Forkhead Transcription Factors / immunology Hepatocyte Growth Factor / genetics, immunology* Immune Tolerance* Interleukin-2 Receptor alpha Subunit / immunology Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Transgenic Spleen / cytology, immunology T-Lymphocytes, Regulatory / cytology, immunology* Th2 Cells / immunology |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Forkhead Transcription Factors; 0/Foxp3 protein, mouse; 0/Interleukin-2 Receptor alpha Subunit; 67256-21-7/Hepatocyte Growth Factor |
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