title: IL-10 delivery by AAV5 vector attenuates inflammation in mice with Pseudomonas pneumonia.
abstract: Lung infections with Pseudomonas aeruginosa and other pathogens in cystic fibrosis (CF) cause progressive airway obstruction and tissue damage, the predominant cause of morbidity and mortality in CF. We investigated whether a recombinant adeno-associated virus type 5 (AAV5) vector expressing murine interleukin (IL)-10 (AAV5.Cbeta-mIL-10), a regulatory/anti-inflammatory cytokine, could decrease airway inflammation in IL-10 knockout mice chronically infected with mucoid P. aeruginosa. Mice that received AAV5.Cbeta-mIL10 through intratracheal inoculation produced IL-10 at an average of 25 000 pg/ml in the epithelial lining fluid (ELF) and 12 000 pg/g-lung tissue 6 weeks post-vector delivery, significantly higher levels than in placebo-treated mice. At 3 days post-infection, proinflammatory cytokines (IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage inhibitory protein (MIP)-1alpha and (KC) in the ELF and lung homogenate were decreased (1-9 folds) in the AAV5.Cbeta-mIL10-treated mice accompanied by less pronounced and more localized neutrophil infiltration in lung sections, when compared with placebo-treated mice. These results suggest that AAV5.Cbeta-mIL10 induces IL-10 levels in the lungs mediating a significant anti-inflammatory response and making AAV-IL-10 gene transfer a potentially useful therapy in the treatment of CF lung disease.
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA. morrowsm@musc.edu
authors.forename: S M
authors.initials: SM
authors.lastname: Buff
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: J N
authors.initials: JN
authors.lastname: McCall
authors.forename: S M
authors.initials: SM
authors.lastname: Caldwell
authors.forename: T W
authors.initials: TW
authors.lastname: Ferkol
authors.forename: T R
authors.initials: TR
authors.lastname: Flotte
authors.forename: I L
authors.initials: IL
authors.lastname: Virella-Lowell
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000628:therapy*; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016753:Interleukin-10 / Q000235:genetics*; D007442:Intubation, Intratracheal; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000628:therapy*; D011552:Pseudomonas Infections / Q000628:therapy*; D011550:Pseudomonas aeruginosa
chemical_list: D016753:Interleukin-10