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The study establishes a human steroid-resistant asthma model using humanized NOG mice, administers rhIL-33 and rhTSLP, and tests dexamethasone suppression.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/novel-humanized-mouse-model-for-steroid-resistant-asthma-letter/444913/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/novel-humanized-mouse-model-for-steroid-resistant-asthma-letter/444913.png","ImageObject",300,407,{"name":42,"@type":43},"SANS","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-02","2026-09-29",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is the main goal of using a humanized mouse model in steroid-resistant asthma?","Question",{"text":63,"@type":64},"To mimic human asthma pathology and enable direct investigation of mechanisms underlying steroid-resistant eosinophilic airway inflammation.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How do rhIL-33 and rhTSLP treatments influence eosinophil infiltration?",{"text":68,"@type":64},"rhIL-33 increases human eosinophil infiltration in bronchoalveolar lavage fluid more than PBS control, and adding rhTSLP sustains eosinophil-related inflammation even under dexamethasone.",{"name":70,"@type":61,"acceptedAnswer":71},"Why does dexamethasone fail to fully suppress the rhIL-33 + rhTSLP phenotype?",{"text":72,"@type":64},"The findings indicate that rhTSLP counteracts steroid suppression of IL-33-induced human asthma phenotype, including eosinophil activation markers and multiple airway 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\nShiho Yamada1,2  | Shuichiro Maruoka1,2  | Shota Toyoshima1,3  | Yusuke Kurosawa1,2  | Ryosuke Ozoe1,2  | Yutaka Kozu1,2  | Kenji Mizumura1,2  | Yoshimichi Okayama1,2,4,5,6  | Ryoji Ito7  | Yasuhiro Gon1,2   \n1Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan | 2Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan | 3Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo,  \nJapan | 4Department of Allergy, Internal Medicine, Misato Kenwa Hospital, Saitama, Japan | 5Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan | 6Advanced Medical Science Research Center, Gunma Paz University, Graduate School of Health Sciences, Takasaki, Gunma, Japan | 7Central Institute for Experimental Medicine and Life Science (CIEM), Kawasaki, Kanagawa, Japan  \nCorrespondence: Shuichiro Maruoka ([maruoka.shuichiro@nihon-u.ac.jp](maruoka.shuichiro@nihon-u.ac.jp)) | Ryoji Ito ([rito@ciea.or.jp](rito@ciea.or.jp))  \nReceived: 16 March 2025 | Revised: 19 July 2025 | Accepted: 3 August 2025  \nFunding: Supported by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI) grant JP24K10563 . AstraZeneca K.K. supported this work and was not involved in the study design, data collection, data analysis, data interpretation, or manuscript writing.  \nKeywords: animal models | asthma | asthma treatment | biologics | immunotherapy clinical | pharmacology and pharmacogenomics  \nTo the Editor,  \nHumanized mice are widely used to mimic human pathological conditions. We previously established a human asthma model using humanized human (h) IL-3/hGM-CSF/hIL-5 transgenic NOD/Shi-scid-IL2rγnull (NOG) mice, which supported the differentiation of human eosinophils, basophils, mast cells, T cells, and B cells, as well as limited numbers of natural killer (NK) cells and type 2 innate lymphoid cells (ILC2) [1] .  \nApproximately 10%–15% of patients with asthma cannot achieve disease control despite receiving high-dose inhaled glucocorticoids plus long-acting β2-agonists or oral corticosteroids. In steroid-resistant asthma, chronic eosinophilic airway inflammation persists and remains unresponsive to corticosteroid treatment. Therefore, targeting eosinophils, particularly with biologics such as anti-IL-5 and IL-5 receptor (IL-5Rα) antibodies, can suppress steroid-resistant eosinophilic inflammation [2] . However, the mechanisms underlying persistent steroidresistant asthma remain unclear due to difficulties in direct human lung analyses.  \nFirst, we established a human steroid-resistant asthma model using our previously reported humanized mice [1] . We  \nintratracheally administered recombinant human (rh) IL-33 (rhIL-33) and thymic stromal lymphopoietin (rhTSLP) to humanized mice. We also administered dexamethasone (Dexa) intraperitoneally over days 0–3 (Figure 1A; details in the Data S1) .  \nHuman eosinophil infiltration in bronchoalveolar lavage fluid (BALF) increased more with the rhIL-33 treatment compared with the PBS control group. Dexa significantly suppressed rhIL-33-induced human eosinophil infiltration, yet did not significantly suppress rhIL-33 + rhTSLP-induced human eosinophil infiltration and human eosinophil-derived neurotoxin (EDN) levels—a marker for human eosinophil activation—compared with rhIL-33 (Figure 1B,C) . Dexa did not suppress rhIL-33 + rhTSLP-induced airway inflammation, goblet cell hyperplasia, type 2 cytokine production, or airway hyperresponsiveness (AHR) (Figure 1D–F) . These data suggest that rhTSLP counteracts steroid suppression of IL-33-induced human asthma phenotype.  \nTo confirm the role of intratracheally administered rhTSLP, we injected an anti-TSLP monoclonal antibody (Details in Data S1) subcutaneously into rhIL-33 plus rhTSLP-admi","cbCaid7fAQPSr2Ga","https://ap.wps.com/l/cbCaid7fAQPSr2Ga","pdf",1192431,"English","# Background\n# Experimental model and treatments\n## Effects on eosinophil infiltration and activation\n## Effects on airway inflammation and hyperresponsiveness\n# Validation of TSLP role\n# Therapeutic implications with biologics","[{\"question\":\"What is the main goal of using a humanized mouse model in steroid-resistant asthma?\",\"answer\":\"To mimic human asthma pathology and enable direct investigation of mechanisms underlying steroid-resistant eosinophilic airway inflammation.\"},{\"question\":\"How do rhIL-33 and rhTSLP treatments influence eosinophil infiltration?\",\"answer\":\"rhIL-33 increases human eosinophil infiltration in bronchoalveolar lavage fluid more than PBS control, and adding rhTSLP sustains eosinophil-related inflammation even under dexamethasone.\"},{\"question\":\"Why does dexamethasone fail to fully suppress the rhIL-33 + rhTSLP phenotype?\",\"answer\":\"The findings indicate that rhTSLP counteracts steroid suppression of IL-33-induced human asthma phenotype, including eosinophil activation markers and multiple airway readouts.\"}]","Novel Humanized Mouse Model for Steroid-Resistant Asthma - Letter | PDF",1790709726]