title: Tolerogenic Dendritic Cells Generated by In Vitro Treatment With SAHA Are Not Stable In Vivo.
abstract: The aim of this study is to examine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can generate dendritic cells (DCs) with a stable tolerogenic phenotype to counteract autoimmune responses in an animal model of multiple sclerosis. We investigated if the tolerogenic potency of DCs could be increased by continuous treatment during in vitro differentiation toward DCs compared to standard 24-h in vitro treatment of already terminally differentiated DCs. We show that in vitro treatment with SAHA reduces the generation of new CD11c(+) DCs out of mouse bone marrow. SAHA-generated DCs show reduced antigen-presenting function as evidenced by a reduction in myelin endocytosis, a decreased MHC II expression, and a failure to upregulate costimulatory molecules upon LPS challenge. In addition, SAHA-generated DCs display a reduction in proinflammatory cytokines and molecules involved in apoptosis induction, inflammatory migration, and TLR signaling, and they are less immunostimulatory compared to untreated DCs. We demonstrated that the underlying mechanism involves a diminished STAT1 phosphorylation and was independent of STAT6 activation. Although in vitro results were promising, SAHA-generated DCs were not able to alleviate the development of experimental autoimmune encephalomyelitis in mice. In vitro washout experiments demonstrated that the tolerogenic phenotype of SAHA-treated DCs is reversible. Taken together, while SAHA potently boosts tolerogenic properties in DCs during the differentiation process in vitro, SAHA-generated DCs were unable to reduce autoimmunity in vivo. Our results imply that caution needs to be taken when developing DC-based therapies to induce tolerance in the context of autoimmune disease.
authors.affiliation: Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Thewissen
authors.forename: Bieke
authors.initials: B
authors.lastname: Broux
authors.forename: Jerome J A
authors.initials: JJ
authors.lastname: Hendriks
authors.forename: Mandy
authors.initials: M
authors.lastname: Vanhees
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.forename: Helena
authors.initials: H
authors.lastname: Slaets
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D039521:CD11c Antigen / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000628:therapy; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D010641:Phenotype; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D039521:CD11c Antigen; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D006877:Hydroxamic Acids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D063308:Myelin-Oligodendrocyte Glycoprotein; D050791:STAT Transcription Factors; D051193:Toll-Like Receptors; D000077337:Vorinostat