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Interleukin-13 as a therapeutic target for allergic asthma tested in human precision-cut lung slices

: Danov, Olga; Jiménez Delgado, Sharon Melissa; Pfennig, Olaf; Forster, Christine; Hohlbaum, Andreas; Audoly, Laurent; Braun, Armin; Sewald, Katherina

American Journal of Respiratory and Critical Care Medicine 189 (2014), Art. A5665
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2014, San Diego/Calif.>
Fraunhofer ITEM ()

Rationale: Asthma is a chronic inflammatory disorder affecting nearly 300 million people. Patients with severe asthma are insensitive to inhaled corticosteroids and require novel therapeutic treatments. Interleukin (IL)-13 is considered as a key cytokine in the pathogenesis of asthma and is a pharmacological target for the treatment of airway inflammation and hyperresponsiveness. Precision-cut lung slices (PCLS) display a suitable ex vivo tissue model that maintain microanatomy and functionality of the respiratory tract. It allows the investigation of the efficacy of new biopharmaceuticals on e.g. cytokine release and bronchoconstriction in human lung tissue. In the present study, the effect of IL-13 on cytokine release and methacholine-induced bronchoconstriction was evaluated in human PCLS.
Antagonists for IL-13 and IL-13 receptor were evaluated as new anti-inflammatory therapeutics.
Methods: PCLS were prepared from human lungs. Cytokine release and airway hyperresponsiveness was measured after incubation of PCLS with 1-100 nM IL-13. Antagonists were assessed by co-incubation of IL-13 and inhibitor for 24 h. Eotaxin-3 and TARC were measured by ELISA. PCLS containing airways were pre-incubated with IL-13 and bronchoconstriction was induced by addition of methacholine. Bronchoconstriction was visualized by videomicroscopy.
Results: We could show that human IL-13 stimulates the secretion of eotaxin-3 and TARC in human PCLS. Both cytokines are biomarkers for eosinophil and T-cell recruitment into lung tissue. IL-13-induced eotaxin-3 and TARC release could be significantly reduced by 100 % in a dose dependent manner by addition of specific inhibitors acting either on the IL-13 ligand itself or the IL-4R.
Conclusions: This study shows that PCLS can be used to mimic IL-13 induced inflammation and airway hyperreagibility in human lungs. The effect of different biological inhibitors developed as asthma therapeutics could be compared on reduction of eotaxin-3 and TARC in human lung tissue.