Suppressive effects of sugar-modified cationic liposome/NF-kappaB decoy complexes on adenovirus vector-induced innate immune responses.
To date, no countermeasures have been developed to overcome adenovirus (Ad) vector-induced innate immune responses in gene therapies that utilize these vectors. In the present study, we attempted to suppress Ad vector-induced innate immune responses and hepatotoxicity by delivering an NF-kappaB decoy to splenic macrophages and dendritic cells, as well as to Kupffer cells in the liver, using sugar-modified cationic liposomes. Pre-injection of the sugar-modified cationic liposome/NF-kappaB decoy complexes reduced serum levels of interleukin (IL)-12, which is a typical inflammatory cytokine induced by Ad vectors, and also reduced hepatotoxicity following Ad vector injection. Electrophoretic mobility shift assay demonstrated a reduction of Ad vector-induced NF-kappaB activation by pre-injection of the sugar-modified cationic liposome/NF-kappaB decoy complexes. Two types of sugar-modified cationic liposomes, fucosylated cationic liposomes (Fuc-liposomes) and mannosylated cationic liposomes (Man-liposomes), were tested in this study. Man-liposomes, which are considered to have greater affinity than Fuc-liposomes for splenocytes, appeared to have superior suppressive effects to those of Fuc-liposomes. Pre-injection of the sugar-modified cationic liposome/NF-kappaB decoy complexes did not inhibit Ad vector-mediated transduction in the organs. This study provides important findings for overcoming Ad vector-induced innate immune responses.
Huang
Haiying
H
Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
Sakurai
Fuminori
F
Higuchi
Yuriko
Y
Kawakami
Shigeru
S
Hashida
Mitsuru
M
Kawabata
Kenji
K
Mizuguchi
Hiroyuki
H
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D005260:Female; D005643:Fucose / Q000737:chemistry; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D006601:Hexoses / Q000737:chemistry; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008358:Mannose / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D006601:Hexoses; D015850:Interleukin-6; D008081:Liposomes; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D010714:Phosphatidylethanolamines; D018664:Interleukin-12; D005643:Fucose; D008156:Luciferases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008358:Mannose