Oka Aiko, Klingler Aiko I, Kidoguchi Masanori, Poposki Julie A, Suh Lydia A, Bai Junqin, Stevens Whitney W, Peters Anju T, Grammer Leslie C, Welch Kevin C, Smith Stephanie S, Conley David B, Schleimer Robert P, Kern Robert C, Tan Bruce K, Fujieda Shigeharu, Okano Mitsuhiro, Kato Atsushi
Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Otolaryngology, International University of Health and Welfare, Narita, Chiba, Japan.
Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.
J Allergy Clin Immunol. 2025 Aug;156(2):463-467.e2. doi: 10.1016/j.jaci.2025.02.031. Epub 2025 Mar 6.
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.
We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS.
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).
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.
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.
胸腺基质淋巴细胞生成素（TSLP）及其功能性裂解产物在鼻息肉（NP）中升高，并通过激活髓样树突状细胞（mDC）和2型固有淋巴细胞（ILC2）在伴鼻息肉的慢性鼻窦炎（CRS）的2型（T2）炎症中发挥重要作用。然而，抗TSLP人源单克隆抗体tezepelumab是否能抑制功能性裂解的TSLP，以及TSLP在无鼻息肉的CRS（CRSsNP）中的作用尚未得到研究。
我们试图研究tezepelumab对CRS中裂解TSLP的影响。
通过定量逆转录聚合酶链反应（RT-PCR）测量31名对照者、118例CRSsNP患者筛窦组织（ET）以及53例CRSwNP患者鼻息肉中TSLP和T2标志物的mRNA表达水平。通过将全长重组TSLP与NP和CRSsNP ET的组织提取物孵育来制备裂解的TSLP。使用外周血单核细胞（PBMC），通过监测趋化因子（mDC的CCL17和CCL22）和细胞因子（ILC2的IL-5和IL-13）的产生，评估tezepelumab对裂解TSLP诱导的炎症的影响。
与非T2型CRSsNP和对照相比，TSLP的mRNA表达水平不仅在NP中升高，在T2型CRSsNP的ET中也升高，并且与CRSsNP中的T2标志物呈正相关（P <.001）。CRSsNP ET也会截短并产生高活性的TSLP产物。tezepelumab可剂量依赖性地抑制全长TSLP以及ET和NP提取物产生的裂解TSLP对mDC和ILC2的激活。
TSLP在CRSsNP和CRSwNP的T2炎症中起作用。用tezepelumab治疗可能通过抑制TSLP的活性形式而使T2型CRS患者受益。
