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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 5

Generation of hu–IL-3/GM-CSF/IL-5 Tg mice.

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Generation of hu–IL-3/GM-CSF/IL-5 Tg mice.
(A) Serum human IL-3, GM-CSF,...
(A) Serum human IL-3, GM-CSF, and IL-5 levels in hu–IL-3/GM-CSF/IL-5 Tg mice (n = 9). (B) Flow cytometric analysis of CD45+ leukocytes and CD66b+CD16– eosinophils among CD45+ cells in the PB of hu–non-Tg, –IL-5 Tg, –IL-3/GM Tg, and –IL-3/GM/IL-5 Tg mice at 10 weeks after transplantation. (C) Cumulative frequencies of leukocytes and eosinophils. Hu–non-Tg (n = 5), –IL-5 Tg (n = 8), –IL-3/GM Tg (n = 9), and –IL-3/GM/IL-5 Tg (n = 8) mice were used. (D) Morphology of human eosinophils. Cytospin samples of CD66b+CD16– eosinophils sorted from the PB of human IL-5 or –IL-3/GM/IL-5 Tg mice were subjected to May-Giemsa staining. (E) Flow cytometry of human Major basic protein (MBP) in CD66b+CD16– eosinophils of hu–IL-5 Tg mice. Mouse IgG1 was used as an isotype control antibody. Representative data from 3 (D) or 4 (E) independent experiments are shown. Original magnification, ×40. Scale bar: 10 μm. Statistical significance was calculated using 1-way ANOVA (C). *P < 0.05, **P < 0.005, and ****P < 0.00005.

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