Tolerogenic dendritic cells produced by lentiviral‐mediated CD 40‐ and interleukin‐23p19‐specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells

Summary 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 DC s ( BMDC s) transduced with lentiviral vectors to permanently expressed shRNA specific for CD 40 ( CD 40 LV ‐ DC s) and/or p19 subunit of interleukin ( IL) ‐23 (p19 LV ‐ DC s) mRNA s in experimental autoimmune encephalomyelitis ( EAE ). In‐vitro studies showed that double‐transduced BMDC s ( CD 40 + p19 LV ‐ DC s) resemble tolerogenic DC s due to profound down‐regulation of CD 40, lower expression of proinflammatory cytokines ( IL ‐6 and IL ‐12), increased IL ‐10 production and stronger stimulation of myelin oligodendrocyte glycoprotein (M OG) 35–55 ‐specific T cells for production of IL ‐10 compared with CD 40 LV ‐ DC s, p19 LV ‐ DC s and BMDC s transduced with control lentiviral vector ( CoLV ‐ DC s). Moreover, injection of transduced CD 40 + p19 LV ‐ BMDC s 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 ‐ DC s‐treated EAE mice. In conclusion, simultaneous knock‐down of CD 40 and IL ‐23 production by BMDC s may represent a promising therapeutic tool for the treatment of IL ‐17‐dependent autoimmune diseases, including multiple sclerosis.