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A humanized mouse model to study asthmatic airway inflammation via the human IL-33/IL-13 axis
Ryoji Ito, … , Mamoru Ito, Satoshi Nunomura
Ryoji Ito, … , Mamoru Ito, Satoshi Nunomura
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e121580. https://doi.org/10.1172/jci.insight.121580.
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Resource and Technical Advance Immunology Inflammation

A humanized mouse model to study asthmatic airway inflammation via the human IL-33/IL-13 axis

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Abstract

Asthma is one of the most common immunological diseases and is characterized by airway hyperresponsiveness (AHR), mucus overproduction, and airway eosinophilia. Although mouse models have provided insight into the mechanisms by which type-2 cytokines induce asthmatic airway inflammation, differences between the rodent and human immune systems hamper efforts to improve understanding of human allergic diseases. In this study, we aim to establish a preclinical animal model of asthmatic airway inflammation using humanized IL-3/GM-CSF or IL-3/GM-CSF/IL-5 Tg NOD/Shi-scid-IL2rγnull (NOG) mice and investigate the roles of human type-2 immune responses in the asthmatic mice. Several important characteristics of asthma — such as AHR, goblet cell hyperplasia, T cell infiltration, IL-13 production, and periostin secretion — were induced in IL-3/GM-CSF Tg mice by intratracheally administered human IL-33. In addition to these characteristics, human eosinophilic inflammation was observed in IL-3/GM-CSF/IL-5 Tg mice. The asthmatic mechanisms of the humanized mice were driven by activation of human Th2 and mast cells by IL-33 stimulation. Furthermore, treatment of the humanized mice with an anti–human IL-13 antibody significantly suppressed these characteristics. Therefore, the humanized mice may enhance our understanding of the pathophysiology of allergic disorders and facilitate the preclinical development of new therapeutics for IL-33–mediated type-2 inflammation in asthma.

Authors

Ryoji Ito, Shuichiro Maruoka, Kaori Soda, Ikumi Katano, Kenji Kawai, Mika Yagoto, Asami Hanazawa, Takeshi Takahashi, Tomoyuki Ogura, Motohito Goto, Riichi Takahashi, Shota Toyoshima, Yoshimichi Okayama, Kenji Izuhara, Yasuhiro Gon, Shu Hashimoto, Mamoru Ito, Satoshi Nunomura

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Figure 7

House dust mite–induced (HDM-induced) airway inflammation model.

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House dust mite–induced (HDM-induced) airway inflammation model.
(A) HSC...
(A) HSC-transferred human IL-5 Tg, –IL-3/GM Tg, –IL-3/GM/IL-5 Tg, and –non-Tg mice were i.t. injected HDM at day 0, 7, and 14 and analyzed at day 17. (B) Quantification of goblet cells in lungs of hu–IL-5 Tg(n = 5 each), hu–IL-3/GM Tg (n = 3 or 6), hu–IL-3/GM/IL-5 Tg (n = 5 or 6), and hu–non-Tg (n = 5 or 4) mice with or without HDM treatment. (C) Levels of human cytokines and chemokines in the BALF of hu–IL-5 Tg(n = 5 or 6), hu–IL-3/GM Tg (n = 3 or 7), hu–IL-3/GM/IL-5 Tg (n = 8 or 7), and hu–non-Tg (n = 6 or 5) mice with or without HDM treatment were analyzed by CBA or ELISA. (D) Levels of human IL-33 in the BALF were analyzed by ELISA. (E) Quantification of total cells and human eosinophils in BALF. (F) Murine eotaxin-1 and -2 in BALF were analyzed by ELISA. Data are represented 6 or 8 human IL-5 Tg, 6 or 10 hu–IL-3/GM Tg, 9 or 11 hu–IL-3/GM/IL-5 Tg, and 8 or 7 hu–non-Tg mice with or without HDM treatment (E–F). Statistical significance was calculated using 1-way ANOVA (E). **P < 0.005.

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