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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 1

Development of a human asthma model using HSC-transferred NOG IL-3/GM-CSF Tg mice.

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Development of a human asthma model using HSC-transferred NOG IL-3/GM-CS...
(A) Schematic of induction of asthmatic airway inflammation using HSC-transferred IL-3/GM Tg mice and intratracheal (i.t.) administration of recombinant human IL-33. (B) Histology of the lungs of hu–IL-3/GM Tg mice after administration of IL-33. Lung sections from hu–IL-3/GM Tg mice treated with or without IL-33 were stained with H&E, as well as anti-CD3 and anti–human mast cell chymase (MCC) antibodies. Each brown dot represents an individual human CD3- or MCC-expressing T cell or mast cell. Representative images from 3 mice are shown. (C) Number of human T cells in BALF of hu–IL-3/GM Tg or non-Tg mice with or without IL-33 administration. (D) Human MCC+ mast cells were quantified in the lung lesions of hu–IL-3/GM Tg mice. HPF, high-power field. (E) Frequency of CD4+ or CD8+ cells among total CD3+ T cells in the BALF or PB of IL-33–treated hu–IL-3/GM Tg mice (n = 4). (F) Left panels showed the flow cytometry data of CD4+ and CD8+ T cells in CD3+ population with or without IL-33 treatment. Right dot plot graphs show the cumulative data of the frequency of CD4+ and CD8+ T cells in the CD3+ population with or without IL-33 treatment. (G) Cell number of CD4+ and CD8+ T cells in lungs and spleen of hu–IL-3/GM Tg mice with or without IL-33 treatment. Data are represented each 3 mice in F and G. Original magnification, ×10 for H&E and CD3, and ×20 for MCC. Scale bar: 100 μm for H&E and CD3; 50 μm for MCC. Statistical significance was calculated using Student’s t test (D, E, and G) and 1-way ANOVA (C). *P < 0.05 and **P < 0.005, ***P < 0.0005, and ****P < 0.00005.

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