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IL-10 delivery by AAV5 vector attenuates inflammation in mice with pseudomonas pneumonia

Gene Therapy volume 17, pages 567–576 (2010)Cite this article

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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.Cβ-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.Cβ-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-1β, tumor necrosis factor (TNF)-α, macrophage inhibitory protein (MIP)-1α and (KC) in the ELF and lung homogenate were decreased (1–9 folds) in the AAV5.Cβ-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.Cβ-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.

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Acknowledgements

We thank the University of Florida Vector Core for production and titering of the AAV5.Cβ-mIL10 vector.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA

    S M Buff, S M Caldwell & I L Virella-Lowell

  2. Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA,

    S M Buff, H Yu, J N McCall, S M Caldwell & I L Virella-Lowell

  3. Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

    T W Ferkol

  4. Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA

    T R Flotte

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  1. S M Buff
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Correspondence to S M Buff.

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This work is supported by NIH awards: NIH grant R01 HL64044 (Ferkol, PI), P01 HL051811 (Flotte, PI), and K08 HL067260 (Virella-Lowell, PI), and the SC Physician's Care Charity for funding of the BioPlex instrument and its reagents (Virella-Lowell, PI). MUSC has an NIH award C06 RR015455 from the Extramural Research Facilities Program of the NCRR for the support of animal facilities.

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Buff, S., Yu, H., McCall, J. et al. IL-10 delivery by AAV5 vector attenuates inflammation in mice with pseudomonas pneumonia. Gene Ther 17, 567–576 (2010). https://doi.org/10.1038/gt.2010.28

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