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Published on: July 7, 2017
IL-10 delivery by AAV5 vector attenuates inflammation in mice with Pseudomonas pneumonia
1Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA. morrowsm@musc.edu
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.
Insights
Gene therapy using AAV5.Cbeta-mIL-10 reduced airway inflammation in cystic fibrosis (CF) mice. This approach delivered interleukin-10 (IL-10), decreasing inflammatory markers and neutrophil infiltration in the lungs.
Area of Science:
- Pulmonary Medicine
- Gene Therapy
- Immunology
Background:
- Cystic Fibrosis (CF) lung infections by Pseudomonas aeruginosa cause progressive airway obstruction and mortality.
- Chronic inflammation is a key driver of lung damage in CF patients.
Purpose of the Study:
- To evaluate the efficacy of a recombinant adeno-associated virus type 5 (AAV5) vector expressing murine interleukin-10 (AAV5.Cbeta-mIL-10) in reducing airway inflammation.
- To assess the impact of AAV-mediated IL-10 delivery on Pseudomonas aeruginosa infection in IL-10 knockout mice.
Main Methods:
- Intratracheal inoculation of AAV5.Cbeta-mIL-10 in IL-10 knockout mice chronically infected with mucoid P. aeruginosa.
- Quantification of IL-10 levels in epithelial lining fluid (ELF) and lung tissue.
- Measurement of proinflammatory cytokines (IL-1beta, TNF-alpha, MIP-1alpha, KC) and assessment of neutrophil infiltration in lung sections.
Main Results:
- AAV5.Cbeta-mIL-10 treatment significantly elevated IL-10 levels in the lungs (25,000 pg/ml in ELF, 12,000 pg/g in lung tissue).
- Proinflammatory cytokine levels were reduced (1-9 fold decrease) in AAV5.Cbeta-mIL-10 treated mice compared to placebo.
- Reduced neutrophil infiltration was observed in the lungs of treated mice, indicating a localized anti-inflammatory effect.
Conclusions:
- AAV5.Cbeta-mIL-10 gene transfer effectively induces therapeutic IL-10 levels in the lungs.
- This approach mediates a significant anti-inflammatory response, reducing key markers of lung inflammation in a CF mouse model.
- AAV-IL-10 gene therapy presents a promising therapeutic strategy for managing lung disease in cystic fibrosis.
