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Human lung tissue provides highly relevant data about efficacy of new anti-asthmatic drugs

 
: Danov, Olga; Jiménez Delgado, Sharon Melissa; Obernolte, Helena; Seehase, Sophie; Dehmel, Susann; Braubach, Peter; Fieguth, Hans-Gerd; Matschiner, Gabriele; Fitzgerald, Mary; Jonigk, Danny; Knauf, Sascha; Pfennig, Olaf; Warnecke, Gregor; Wichmann, Judy; Braun, Armin; Sewald, Katherina

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Volltext urn:nbn:de:0011-n-5239598 (1.5 MByte PDF)
MD5 Fingerprint: 305cb21fbb9b3d99d40f3d831088969a
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Erstellt am: 13.12.2018


PLoS one. Online journal 13 (2018), Nr.11, Art. e0207767, 19 S.
http://www.pubmedcentral.nih.gov/tocrender.fcgi?action=archive&journal=440
ISSN: 1932-6203
Englisch
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer ITEM ()

Abstract
Subgroups of patients with severe asthma are insensitive to inhaled corticosteroids and require novel therapies on top of standard medical care. IL-13 is considered one of the key cytokines in the asthma pathogenesis, however, the effect of IL-13 was mostly studied in rodents. This study aimed to assess IL-13 effect in human lung tissue for the development of targeted therapy approaches such as inhibition of soluble IL-13 or its receptor IL-4Rα subunit. Precision-cut lung slices (PCLS) were prepared from lungs of rodents, non-human primates (NHP) and humans. Direct effect of IL-13 on human lung tissue was observed on inflammation, induction of mucin5AC, and airway constriction induced by methacholine and visualized by videomicroscopy. Anti-inflammatory treatment was evaluated by co-incubation of IL-13 with increasing concentrations of IL-13/IL-13 receptor inhibitors. IL-13 induced a two-fold increase in mucin5AC secretion in human bronchial tissue. Additionally, IL-13 induced release of proinflammatory cytokines eotaxin-3 and TARC in human PCLS. Anti-inflammatory treatment with four different inhibitors acting either on the IL-13 ligand itself (anti-IL-13 antibody, similar to Lebrikizumab) or the IL-4Rα chain of the IL-13/IL-4 receptor complex (anti-IL-4Rα #1, similar to AMG 317, and #2, similar to REGN668) and #3 PRS-060 (a novel anticalin directed against this receptor) could significantly attenuate IL-13 induced inflammation. Contrary to this, IL-13 did not induce airway hyperresponsiveness (AHR) in human and NHP PCLS, although it was effective in rodent PCLS. Overall, this study demonstrates that IL-13 stimulation induces production of mucus and biomarkers of allergic inflammation in human lung tissue ex-vivo but no airway hyperresponsiveness. The results of this study show a more distinct efficacy than known from animals models and a clear discrepancy in AHR induction. Moreover, it allows a translational approach in inhibitor profiling in human lung tissue.

: http://publica.fraunhofer.de/dokumente/N-523959.html