title: Transient pretreatment with glucocorticoid ablates innate toxicity of systemically delivered adenoviral vectors without reducing efficacy.
abstract: More than 300 human clinical trials utilize recombinant adenoviruses (rAds) as a gene transfer vector, confirming that rAds continue to be of high clinical interest. A primary weakness of rAds is their known propensity to trigger an innate, proinflammatory immune response rapidly after high-dose, systemic administration. In this study, we investigated what affects that pre-emptive treatment with anti-inflammatory glucocorticoids might have upon Ad vector-triggered inflammatory immune responses. We found that a simple pretreatment regimen with Dexamethasone (DEX) can significantly reduce most Ad-induced innate immune responses. DEX prevented rAd induction of systemic cytokine/chemokine releases in a dose-dependent fashion, with higher dosages preventing rAd induction of acute thrombocytopenia, endothelial cell activation, proinflammatory gene induction, and leukocyte infiltration into transduced organs. Transient glucocorticoid pretreatment also significantly reduced rAd-induced adaptive immune responses, including a decreased induction of Ad-neutralizing antibodies (NAbs). Importantly, use of DEX did not reduce the efficacy of rAd-mediated gene transduction nor rAd-derived transgene expression. Our results demonstrate that a simple, pre-emptive and transient glucocorticoid pretreatment is a viable approach to reduce rAd-associated acute toxicities that currently limit the use of Ad vectors in systemic clinical applications.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48823, USA.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: McBride
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Schuldt
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.forename: Tyler
authors.initials: T
authors.lastname: Voss
authors.forename: Junping
authors.initials: J
authors.lastname: Wei
authors.forename: Matthew
authors.initials: M
authors.lastname: Bujold
authors.forename: William
authors.initials: W
authors.lastname: Nance
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors / Q000009:adverse effects*; D007113:Immunity, Innate / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic
chemical_list: D018836:Inflammation Mediators; D003907:Dexamethasone