title: Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance.
abstract: It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.
authors.affiliation: Department of Pediatrics and Department of Emergency, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Yan
authors.identifier: 0000-0002-1391-2602
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Xiao
authors.identifier: 0000-0002-7147-8365
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Zhiwei
authors.identifier: 0000-0002-4601-0584
authors.initials: Z
authors.lastname: Su
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Xingyan
authors.identifier: 0000-0002-7478-1984
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Huijie
authors.identifier: 0000-0003-3101-3923
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Chunfen
authors.identifier: 0000-0002-1189-0585
authors.initials: C
authors.lastname: Mo
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Yang
authors.identifier: 0000-0003-4316-8885
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Yantang
authors.identifier: 0000-0003-0854-4988
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D018417:Th1 Cells / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology*
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib