Abstract Details

Title Upregulation of Glucocorticoid-Induced Leucine Zipper by Hepatocyte Growth Factor Promotes Tolerogenic Dendritic Cells and Inhibits Experimental Autoimmune Encephalomyelitis

Topic MS and Related Diseases

Presentation(s) S50 - (-)

Poster/Presentation
Number 006

Objective

Background We previously showed that CNS-restricted expression of HGF, a factor known for both neuronal and oligodendrocytic protective properties, reduced the severity of EAE (Benkhoucha M. et al., PNAS, 2010). HGF decreased EAE immunopathogenesis by promoting tolerogenic dendritic cells (DCs), professional antigen-presenting cells that play a critical role in the maintenance of self-tolerance in both the CNS and periphery. Expression of glucocorticoid-induced leucine zipper (GILZ), a transcriptional regulator, was reported to correlate with the regulatory activity of tolerogenic DCs and to mediate the immunosuppressive effects of glucocorticoids (Cohen N. et al., Blood, 2005), conferring a possible mechanism by which HGF could exert regulatory activities on DCs.

Design/Methods HGF (50 [mu]g) treatment was applied s.c. two days before EAE induction (myelin oligodendrocyte glycoprotein peptide 35-55). DC functions were evaluated ex vivo. Using DCs in which GILZ expression was selectively suppressed, we assessed the ability of HGF to induce tolerogenic DCs.

Results Mice treated with HGF developed reduced disease and had in the periphery decreased frequencies of both Th1 and Th17 cells but increased proportion of regulatory T cells. DCs from HGF-treated mice produced high levels of GILZ. RNA interference-mediated knock-down approach demonstrated that GILZ is critical for HGF in driving differentiation of tolerogenic DCs and generation of regulatory T cells. Further, using adoptive transfer experiments, we established that HGF treatment of DCs from wild-type, but not from GILZ knock-out mice, conferred significant protection to recipient mice with established EAE.

Conclusions These results indentify GILZ as a critical factor for effective suppression of T-cell-mediated CNS inflammation by HGF via the induction of tolerogenic DCs, a mechanism that may be exploited for therapeutic benefit in pathology of autoimmune diseases such as MS.

Authors/Disclosures
Nicolas Molnarfi PRESENTER	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.
David H. Margolin, MD, PhD (Genzyme Corporation)	Dr. Margolin has received personal compensation for serving as an employee of uniQure, Inc.. Dr. Margolin has stock in Cerevance, Inc. Dr. Margolin has stock in Datacubed Health. Dr. Margolin has stock in uniQure, Inc.. Dr. Margolin has received intellectual property interests from a discovery or technology relating to health care.

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