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Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells

Funakoshi, Hiroshi
Nakamura, Toshikazu
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 AnimalsAntigen PresentationCell ProliferationCytokines/biosynthesis/immunologyDendritic Cells/immunologyEncephalomyelitis, Autoimmune, Experimental/genetics/immunologyForkhead Transcription Factors/immunologyHepatocyte Growth Factor/genetics/immunologyImmune ToleranceInterleukin-2 Receptor alpha Subunit/immunologyLymphocyte ActivationMiceMice, Inbred C57BLMice, TransgenicSpleen/cytology/immunologyT-Lymphocytes, Regulatory/cytology/immunologyTh2 Cells/immunology
PMID: 20332205
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Research group Scléroses en plaques, neuroimmunologie, encéphalite autoimmune expérimentale (843)
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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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