title: Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.
abstract: Excessive complement activation can result in extreme tissue damage and systemic inflammatory responses, similar to innate immune responses rapidly elicited after systemic adenovirus (Ad) injections. To determine if Ad interactions with the complement system impact upon Ad-induced innate immune responses, we injected Ad into complement-deficient, C3-knockout mice (C3-KO) or wild-type mice (WT) and quantitatively compared multiple anti-Ad innate immune responses in both strains of mice. In Ad-treated WT mice, we noted rapid increases in plasma KC levels (1 h post injection), followed by increases in IL-6, IFN-gamma, RANTES, IL-12(p40), IL-5, G-CSF, and GM-CSF and subsequently thrombocytopenia. Conversely, in Ad-treated C3-KO mice, many of these inflammatory responses were significantly blunted, including the avoidance of Ad-induced thrombocytopenia. Global liver transcriptome responses in Ad-treated WT mice were assessed by RT-PCR-validated gene array analysis and were found to be also significantly affected by the lack of complement activity in Ad-treated C3-KO mice. Finally, our results confirmed the ability of high dose Ads to transduce hepatocytes despite a lack of complement activity. In summary, Ad interactions with the mammalian complement system are significant and likely initiate and/or exacerbate many of the inflammatory responses noted after systemic Ad injections.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Kiang
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Everett
authors.forename: Delila
authors.initials: D
authors.lastname: Serra
authors.forename: Haixiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Frank
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005822:Genetic Vectors / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D003176:Complement C3; D016207:Cytokines; D001616:beta-Galactosidase