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

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.

Heat shock protein 70 is a positive regulator of airway inflammation and goblet cell hyperplasia in a mouse model of allergic airway inflammation

“…These findings suggest that the loss of Hsp70 reduces allergeninduced Th2 immune responses in the lung via T cell activation rather than acting through structural cells or APCs. Also, we addressed whether Hsp70 has any modulatory effect on IL-13induced AHR using the PCLS contraction assay (27)(28)(29). Lung slices were prepared from naive WT mice and then incubated for 24 h with a recombinant mouse IL-13 to induce AHR with or without YM-08, an Hsp70 small-molecule inhibitor (30).…”

IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways

“…Importantly however, very few studies have translated these animal data into human airways. [16][17][18][19] The few reports using human tissues create a scattered picture because of the different experimental models used (isolated bronchi vs precision cut lung slices) or varying protocols (eg, duration of exposure). The 4 key cytokines addressed in the current investigation, IL-4, IL-5, IL-13, and IL-17A, have not previously been compared in the same study in human airways.…”

Modifying and Integrating in vitro and ex vivo Respiratory Models for Inhalation Drug Screening

“…Thus, PCLS have emerged as a powerful research tool and offer a more complex mechanistic understanding of drug interactions with the multicellular and multidimensional properties of a lung (Hess et al, 2016;Hansen et al, 2016;Cedilak et al, 2019;Liu et al, 2019). In addition, PCLS provide opportunities to assess preclinical, translational studies that determine therapeutic concentrations and efficacies of drugs delivered to different lung regions and have also allowed for cross-species comparisons-with PCLS reportedly prepared from a variety of species including rodent, sheep and human lung tissue (Danov et al, 2018;Lehmann et al, 2018;Yilmaz et al, 2019).…”

“…PCLS have been utilized in studies as pre-validation platforms to screen compound toxicity and drug efficacy (Hess et al, 2016;Danov et al, 2018;Cedilak et al, 2019). Drug delivery to ex vivo PCLS is often via submersion in drug-containing medium (Nassimi et al, 2009;Neuhaus et al, 2013Neuhaus et al, , 2014Paranjpe et al, 2013) or direct liquid infusion (via culture medium) to the airway (Hess et al, 2016) as the ventilated delivery of compounds (to mimic inhaled delivery) to PCLS models is currently unattainable.…”