Abstract Details

Title Systemic Treatment with Hepatocyte Growth Factor Suppresses the Development of Experimental Autoimmune Encephalomyelitis and Induces the Differentiation of Regulatory Dendritic Cells

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 167

Objective

Background BACKGROUND: HGF is a multifunctional cytokine that suppresses inflammation in a variety of disease models. In EAE, a common model of Multiple Sclerosis (MS), we have demonstrated that overexpression of neuronal HGF attenuated disease progression via at least anti-inflammatory signals (Benkhoucha M. et al., PNAS, 2010). As studies further identified HGF as a novel neurotrophic and neuroregenerative factor in mouse MS models (Bai L. et al., Nat Neurosci., 2012), the mechanisms through which HGF exerts its beneficial effects in EAE remain only partially elucidated. We addressed here the effects of systemic administration of HGF on peripheral immune responses and EAE progression.

Design/Methods DESIGN/METHODS: EAE was induced by myelin oligodendrocyte glycoprotein peptide 35-55. Gelatin microspheres incorporating HGF (50 [mu]g) or PBS (vehicle) were s.c. injected into mice before disease induction. Disease severity was assessed daily. Peripheral immune T cell responses, CNS inflammation and demyelination were evaluated at peak disease.

Results RESULTS: HGF by prevention treatment reduced clinical manifestations, perivascular cell infiltration and demyelination in the spinal cord of EAE mice. In the periphery, HGF-treated mice had reduced frequencies of encephalitogenic T helper (Th)1 and Th17 T cells but increased fraction of regulatory T cells. Dendritic cells (DCs) from HGF-treated mice produced low levels of the pro-inflammatory cytokine interleukin (IL)-12 but higher levels of the immunossupressive program death ligand (PD-L)1 molecules. Complementary in vitro studies demonstrated that HGF-treated DCs suppressed autoreactive Th1 and Th17 cells and promoted IL-10-producing regulatory T cells.

Conclusions CONCLUSIONS: These results suggest that HGF exerts a peripheral anti-inflammatory effect through the generation of tolerogenic DCs, leading to reduced CNS injury. By coupling immunosuppressive, neurorepair properties, HGF occurs to be a promising candidate for the treatment of inflammatory demyelinating neurodegenerative diseases such as MS.

Authors/Disclosures
Nicolas Molnarfi PRESENTER	No disclosure on file
Fulton Velez	No disclosure on file
	No disclosure on file
Marie-Laure Santiago-Raber, PhD	No disclosure on file
	No disclosure on file
Patrice LaLive, MD	Dr. LaLive has nothing to disclose.

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