Novel humanized immune cells lead to development of refractory asthma model mouse

A research group led by Research Assistant Shiho Yamada, Associate Professor Shuichiro Maruoka, and Professor Yasuhiro Gon of the Division of Respiratory Medicine, Department of Internal Medicine at Nihon University School of Medicine, along with Lab Head Ryoji Ito of the Human Disease Model Laboratory, Central Institute for Experimental Medicine and Life Science (CIEM), announced on September 24 that they have established a humanized mouse model with a human immune system that replicates "refractory asthma" resistant to conventional steroid treatment. Using this model mouse, they verified the efficacy of anti-IL-5 receptor antibodies targeting human eosinophils and confirmed suppression of human eosinophilic inflammation. The model is expected to be applied as a preclinical evaluation tool for novel therapeutics. The results were published in Allergy on August 23.

Asthma is characterized by paroxysmal respiratory distress caused by airway narrowing in response to various stimuli due to hypersensitivity resulting from chronic airway inflammation, affecting approximately 300 million people worldwide. About 10% of patients are severe refractory asthma patients who do not respond to steroid treatment, and development of therapeutic approaches is needed because chronic eosinophilic airway inflammation persists in these patients.

The research group had previously developed immunodeficient mice (NOG-Triple Tg) expressing three types of human-derived cytokines (IL-3, GM-CSF, IL-5). By transplanting human hematopoietic stem cells into these mice, human immune cells including human eosinophils were reconstituted, meaning they had developed the world's first humanized mouse capable of reproducing human asthma pathology by administering IL-33.

In this study, the research group created humanized mice by transplanting human hematopoietic stem cells into NOG-Triple Tg mice and simultaneously administered two types of cytokines (human IL-33 and TSLP). TSLP is a cytokine secreted from epithelial cells that is involved in allergic inflammation and steroid resistance.

As a result, these mice successfully reproduced the pathology of steroid-resistant refractory asthma. Human eosinophils, which normally decrease with steroid (dexamethasone) administration, did not significantly decrease, and goblet cell hyperplasia was not suppressed.

Furthermore, when the researchers verified the efficacy of benralizumab (anti-IL-5Rα antibody), an existing therapeutic used for severe asthma treatment that specifically depletes eosinophils, human eosinophilic inflammation in the lungs and goblet cell hyperplasia were suppressed.

Because the model shows inflammatory responses similar to clinical symptoms when asthma is induced, it serves as a useful model mouse for elucidating the pathogenesis of refractory asthma. It is expected to be utilized for verifying the mechanisms of action and limitations of therapeutics.

Maruoka commented: "We believe this humanized mouse model of refractory asthma is a tool that can be utilized for preclinical research, such as elucidating new pathologies of human refractory asthma in local lung tissue that has been difficult to analyze until now and examining the effects of novel drugs. This model can be applied not only to asthma but also to various immune-related diseases, and patient-specific humanized mice can be created by transplanting patient-derived peripheral blood stem cells, so we can expect developments that contribute to establishing truly personalized medicine."

Journal Information
Publication: Allergy
Title: Novel Humanized Mouse Model for Steroid-Resistant Asthma
DOI: 10.1111/all.70012