Aiko Oka, Aiko I Klingler, Masanori Kidoguchi, Julie A Poposki, Lydia A Suh, Junqin Bai, Whitney W Stevens, Anju T Peters, Leslie C Grammer, Kevin C Welch, Stephanie S Smith, David B Conley, Robert P Schleimer, Robert C Kern, Bruce K Tan, Shigeharu Fujieda, Mitsuhiro Okano, Atsushi Kato
{"title":"Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis.","authors":"Aiko Oka, Aiko I Klingler, Masanori Kidoguchi, Julie A Poposki, Lydia A Suh, Junqin Bai, Whitney W Stevens, Anju T Peters, Leslie C Grammer, Kevin C Welch, Stephanie S Smith, David B Conley, Robert P Schleimer, Robert C Kern, Bruce K Tan, Shigeharu Fujieda, Mitsuhiro Okano, Atsushi Kato","doi":"10.1016/j.jaci.2025.02.031","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Thymic stromal lymphopoietin (TSLP) and its functional cleavage products are elevated in nasal polyps (NPs) and play important roles in type 2 (T2) inflammation in chronic rhinosinusitis (CRS) with NPs (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human monoclonal antibody against TSLP, inhibits functional cleaved TSLP and the role of TSLP in CRS without NPs (CRSsNP) have not been studied.</p><p><strong>Objective: </strong>To investigate the effects of tezepelumab on cleaved TSLP in CRS.</p><p><strong>Methods: </strong>Messenger RNAs for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 CRSsNP, and NPs from 53 CRSwNP were measured by quantitative RT-PCR. Cleaved TSLP was prepared from full-length recombinant TSLP by incubation with tissue extracts of NPs and CRSsNP ETs. The effects of tezepelumab on cleaved TSLP-induced inflammation were evaluated using peripheral blood mononuclear cells by monitoring production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s).</p><p><strong>Results: </strong>The mRNA for TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared to non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P<0.001). CRSsNP ET also truncated and created highly active TSLP products. The activation of mDCs and ILC2s by full-length TSLP and cleaved TSLP created by ET and NP extracts were dose-dependently inhibited by tezepelumab.</p><p><strong>Conclusions: </strong>TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit T2 CRS patients by inhibiting active forms of TSLP.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaci.2025.02.031","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Thymic stromal lymphopoietin (TSLP) and its functional cleavage products are elevated in nasal polyps (NPs) and play important roles in type 2 (T2) inflammation in chronic rhinosinusitis (CRS) with NPs (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human monoclonal antibody against TSLP, inhibits functional cleaved TSLP and the role of TSLP in CRS without NPs (CRSsNP) have not been studied.
Objective: To investigate the effects of tezepelumab on cleaved TSLP in CRS.
Methods: Messenger RNAs for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 CRSsNP, and NPs from 53 CRSwNP were measured by quantitative RT-PCR. Cleaved TSLP was prepared from full-length recombinant TSLP by incubation with tissue extracts of NPs and CRSsNP ETs. The effects of tezepelumab on cleaved TSLP-induced inflammation were evaluated using peripheral blood mononuclear cells by monitoring production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s).
Results: The mRNA for TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared to non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P<0.001). CRSsNP ET also truncated and created highly active TSLP products. The activation of mDCs and ILC2s by full-length TSLP and cleaved TSLP created by ET and NP extracts were dose-dependently inhibited by tezepelumab.
Conclusions: TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit T2 CRS patients by inhibiting active forms of TSLP.
期刊介绍：
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.
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