Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis

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

Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 nasal polyps (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human mAb against TSLP, inhibits functional cleaved TSLP and also the role of TSLP in CRS without nasal polyps (CRSsNP) have not yet been studied. Objective: We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS. Methods: The mRNA expression levels for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 patients with CRSsNP and in NPs from 53 patients with 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 PBMCs by monitoring the production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s). Results: The mRNA expression level of TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared with non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P < .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 was dose-dependently inhibited by tezepelumab. Conclusions: TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit patients with T2 CRS by inhibiting active forms of TSLP.

Original language	English (US)
Journal	Journal of Allergy and Clinical Immunology
DOIs	https://doi.org/10.1016/j.jaci.2025.02.031
State	Accepted/In press - 2025

Funding

This research was supported in part by AstraZeneca, National Institutes of Health grants (grant nos. P01AI145818 and R01AI137174), the Japan Agency for Medical Research and Development (no. JP23jf0126005), the Uehara Memorial Foundation, and the Ernest S. Bazley Foundation.We gratefully acknowledge Mr James Norton, Ms Aditi Agarwal, and Ms Julia H. Huang (Northwestern University Feinberg School of Medicine, Chicago, Ill) for their skillful technical assistance. We also gratefully acknowledge the Northwestern University NUSeq Core Facility for its support with quantitative RT-PCR.

Keywords

CRSsNP
CRSwNP
T2 inflammation
TSLP
Tezepelumab
chronic rhinosinusitis
nasal polyps
posttranslational modification

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2025.02.031

Cite this

Oka, A., Klingler, A. I., Kidoguchi, M., Poposki, J. A., Suh, L. A., Bai, J., Stevens, W. W., Peters, A. T., Grammer, L. C., Welch, K. C., Smith, S. S., Conley, D. B., Schleimer, R. P., Kern, R. C., Tan, B. K., Fujieda, S., Okano, M., & Kato, A. (Accepted/In press). Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2025.02.031

@article{cee824db2afb4599ae997229b4250855,

title = "Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis",

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 nasal polyps (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human mAb against TSLP, inhibits functional cleaved TSLP and also the role of TSLP in CRS without nasal polyps (CRSsNP) have not yet been studied. Objective: We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS. Methods: The mRNA expression levels for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 patients with CRSsNP and in NPs from 53 patients with 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 PBMCs by monitoring the production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s). Results: The mRNA expression level of TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared with non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P < .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 was dose-dependently inhibited by tezepelumab. Conclusions: TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit patients with T2 CRS by inhibiting active forms of TSLP.",

keywords = "CRSsNP, CRSwNP, T2 inflammation, TSLP, Tezepelumab, chronic rhinosinusitis, nasal polyps, posttranslational modification",

author = "Aiko Oka and Klingler, {Aiko I.} and Masanori Kidoguchi and Poposki, {Julie A.} and Suh, {Lydia A.} and Junqin Bai and Stevens, {Whitney W.} and Peters, {Anju T.} and Grammer, {Leslie C.} and Welch, {Kevin C.} and Smith, {Stephanie S.} and Conley, {David B.} and Schleimer, {Robert P.} and Kern, {Robert C.} and Tan, {Bruce K.} and Shigeharu Fujieda and Mitsuhiro Okano and Atsushi Kato",

note = "Publisher Copyright: {\textcopyright} 2025 American Academy of Allergy, Asthma & Immunology",

year = "2025",

doi = "10.1016/j.jaci.2025.02.031",

language = "English (US)",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

}

Oka, A, Klingler, AI, Kidoguchi, M, Poposki, JA, Suh, LA, Bai, J , Stevens, WW , Peters, AT , Grammer, LC , Welch, KC , Smith, SS , Conley, DB , Schleimer, RP , Kern, RC , Tan, BK, Fujieda, S, Okano, M & Kato, A 2025, 'Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2025.02.031

TY - JOUR

T1 - Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis

AU - Oka, Aiko

AU - Klingler, Aiko I.

AU - Kidoguchi, Masanori

AU - Poposki, Julie A.

AU - Suh, Lydia A.

AU - Bai, Junqin

AU - Stevens, Whitney W.

AU - Peters, Anju T.

AU - Grammer, Leslie C.

AU - Welch, Kevin C.

AU - Smith, Stephanie S.

AU - Conley, David B.

AU - Schleimer, Robert P.

AU - Kern, Robert C.

AU - Tan, Bruce K.

AU - Fujieda, Shigeharu

AU - Okano, Mitsuhiro

AU - Kato, Atsushi

PY - 2025

Y1 - 2025

N2 - 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 nasal polyps (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human mAb against TSLP, inhibits functional cleaved TSLP and also the role of TSLP in CRS without nasal polyps (CRSsNP) have not yet been studied. Objective: We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS. Methods: The mRNA expression levels for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 patients with CRSsNP and in NPs from 53 patients with 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 PBMCs by monitoring the production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s). Results: The mRNA expression level of TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared with non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P < .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 was dose-dependently inhibited by tezepelumab. Conclusions: TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit patients with T2 CRS by inhibiting active forms of TSLP.

AB - 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 nasal polyps (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human mAb against TSLP, inhibits functional cleaved TSLP and also the role of TSLP in CRS without nasal polyps (CRSsNP) have not yet been studied. Objective: We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS. Methods: The mRNA expression levels for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 patients with CRSsNP and in NPs from 53 patients with 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 PBMCs by monitoring the production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s). Results: The mRNA expression level of TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared with non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P < .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 was dose-dependently inhibited by tezepelumab. Conclusions: TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit patients with T2 CRS by inhibiting active forms of TSLP.

KW - CRSsNP

KW - CRSwNP

KW - T2 inflammation

KW - TSLP

KW - Tezepelumab

KW - chronic rhinosinusitis

KW - nasal polyps

KW - posttranslational modification

UR - http://www.scopus.com/inward/record.url?scp=105000923114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=105000923114&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2025.02.031

DO - 10.1016/j.jaci.2025.02.031

M3 - Article

C2 - 40057283

AN - SCOPUS:105000923114

SN - 0091-6749

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

ER -

Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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