Hier finden Sie wissenschaftliche Publikationen aus den Fraunhofer-Instituten.

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

Fulltext urn:nbn:de:0011-n-5239598 (1.5 MByte PDF)
MD5 Fingerprint: 305cb21fbb9b3d99d40f3d831088969a
(CC) by
Created on: 13.12.2018

PLoS one. Online journal 13 (2018), No.11, Art. e0207767, 19 pp.
ISSN: 1932-6203
Journal Article, Electronic Publication
Fraunhofer ITEM ()

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.