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Title

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells
Authors
Benkhoucha, Mahdia
Santiago-Raber, Marie-Laure
Schneiter, Gregory
Chofflon, Michel
Funakoshi, Hiroshi
Nakamura, Toshikazu
Lalive d'Epinay, Patrice
Published in Proceedings of the National Academy of Sciences. 2010, vol. 107, no. 14, p. 6424-9
Abstract 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.
Keywords 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
Identifiers
PMID: 20332205
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Article (Published version) (999 Kb) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research group Scléroses en plaques, neuroimmunologie, encéphalite autoimmune expérimentale (843)
Citation
(ISO format) 		BENKHOUCHA, Mahdia et al. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. In: Proceedings of the National Academy of Sciences, 2010, vol. 107, n° 14, p. 6424-9. doi: 10.1073/pnas.0912437107 https://archive-ouverte.unige.ch/unige:31021

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Deposited on : 2013-11-13

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