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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/21732

Title: Tolerogenic Dendritic Cells Generated by In Vitro Treatment With SAHA Are Not Stable In Vivo
Authors: Thewissen, Kristof
Broux, Bieke
Hendriks, Jerome J. A.
Vanhees, Mandy
Stinissen, Piet
Slaets, Leen
Hellings, Niels
Issue Date: 2016
Citation: Cell transplantation, 25 (6), p. 1207-1218
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.
Notes: [Thewissen, Kristof; Broux, Bieke; Hendriks, Jerome J. A.; Stinissen, Piet; Slaets, Helena; Hellings, Niels] Hasselt Univ, Biomed Res Inst, Diepenbeek, Belgium. [Thewissen, Kristof; Broux, Bieke; Hendriks, Jerome J. A.; Stinissen, Piet; Slaets, Helena; Hellings, Niels] Transnat Univ Limburg, Sch Life Sci, Diepenbeek, Belgium. [Vanhees, Mandy] Univ Ghent, Dept Clin Chem Microbiol & Immunol, B-9000 Ghent, Belgium.
URI: http://hdl.handle.net/1942/21732
DOI: 10.3727/096368915X690305
ISI #: 000377847700015
ISSN: 0963-6897
Category: A1
Type: Journal Contribution
Validation: ecoom, 2017
Appears in Collections: Research publications

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