title: A super TLR agonist to improve efficacy of dendritic cell vaccine in induction of anti-HCV immunity.
abstract: Persistent infections caused by pathogens such as hepatitis C virus are major human diseases with limited or suboptimal prophylactic and therapeutic options. Given the critical role of dendritic cell (DC) in inducing immune responses, DC vaccination is an attractive means to prevent and control the occurrence and persistence of the infections. However, DCs are built-in with inherent negative regulation mechanisms which attenuate their immune stimulatory activity and lead to their ineffectiveness in clinical application. In this study, we developed a super DC stimulant that consists of a modified, secretory Toll-like Receptor (TLR)-5 ligand and an inhibitor of the negative regulator, suppressor of cytokine sinaling-1 (SOCS1). We found that expressing the super stimulant in DCs is drastically more potent and persistent than using the commonly used DC stimuli to enhance the level and duration of inflammatory cytokine production by both murine and human DCs. Moreover, the DCs expressing the super stimulant are more potent to provoke both cellular and humoral immune responses against hepatitis C virus (HCV) antigen in vivo. Thus, the strategy capable of triggering and sustaining proinflammatory status of DCs may be used to boost efficiency of DC vaccine in preventing and combating the persistent infection of HCV or other chronic viruses.
authors.affiliation: Norris Comprehensive Cancer Center, Department of Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Bangxing
authors.initials: B
authors.lastname: Hong
authors.forename: Sung-Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Song
authors.forename: Lindsey
authors.initials: L
authors.lastname: Jones
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Xue F
authors.initials: XF
authors.lastname: Huang
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D044127:Epigenesis, Genetic; D005408:Flagellin / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000517:prevention & control; D006657:Histones / Q000378:metabolism; D006801:Humans; D007109:Immunity; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D007114:Immunization; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology; D034741:RNA, Small Interfering / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists*; D016896:Treatment Outcome; D014761:Viral Hepatitis Vaccines / Q000276:immunology*
chemical_list: D016207:Cytokines; D006657:Histones; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; D014761:Viral Hepatitis Vaccines; D005408:Flagellin