title: Tolerogenic dendritic cells produced by lentiviral-mediated CD40- and interleukin-23p19-specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells.
abstract: Down-regulation of soluble or membrane-bound co-stimulatory molecules by RNAi in dendritic cells can prevent the activation of immune responses. Therefore, this study was designed to evaluate the therapeutic efficacy of bone marrow-derived DCs (BMDCs) transduced with lentiviral vectors to permanently expressed shRNA specific for CD40 (CD40LV-DCs) and/or p19 subunit of interleukin (IL)-23 (p19LV-DCs) mRNAs in experimental autoimmune encephalomyelitis (EAE). In-vitro studies showed that double-transduced BMDCs (CD40(+) p19LV-DCs) resemble tolerogenic DCs due to profound down-regulation of CD40, lower expression of proinflammatory cytokines (IL-6 and IL-12), increased IL-10 production and stronger stimulation of myelin oligodendrocyte glycoprotein (MOG)35-55 -specific T cells for production of IL-10 compared with CD40LV-DCs, p19LV-DCs and BMDCs transduced with control lentiviral vector (CoLV-DCs). Moreover, injection of transduced CD40(+) p19LV- BMDCs in EAE mice resulted in more reduction in clinical score, significant reduction in IL-17 or increased production of IL-10 by mononuclear cells derived from the lymph nodes or spinal cord compared with CoLV-DCs-treated EAE mice. In conclusion, simultaneous knock-down of CD40 and IL-23 production by BMDCs may represent a promising therapeutic tool for the treatment of IL-17-dependent autoimmune diseases, including multiple sclerosis.
authors.affiliation: Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kalantari
authors.forename: M H
authors.initials: MH
authors.lastname: Karimi
authors.forename: B
authors.initials: B
authors.lastname: Ciric
authors.forename: Y
authors.initials: Y
authors.lastname: Yan
authors.forename: A
authors.initials: A
authors.lastname: Rostami
authors.forename: E
authors.initials: E
authors.lastname: Kamali-Sarvestani
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D034622:RNA Interference / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10
keywords: CD40; IL-23p19; RNAi; dendritic cell; lentiviral vector