Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma

Shikotra, Aarti; Choy, David F.; Ohri, Chandra; Doran, Emma; Butler, Claire A.; Hargadon, Beverley; Shelley, Maria; Abbas, Alexander R.; Austin, Cary D.; Jackman, Janet; Wu, Lawren C.; Heaney, Liam G.; Arron, Joseph R.; Bradding, Peter

doi:10.1016/j.jaci.2011.08.031

Cited by 283 publications

(254 citation statements)

References 37 publications

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“…This is relevant to clinical findings that levels of TSLP in airway epithelia and lamina propria are elevated in patients with severe 22 or fatal asthma 27 . TSLP expression can be induced in bronchial epithelial cells in response to various danger signals including protease antigens such as those of the house dust mite 37 .…”

Section: Discussionmentioning

confidence: 91%

“…TSLP is especially relevant to corticosteroid resistance in inflamed airways. Bronchial epithelial cells produce TSLP and the amounts of TSLP in the lung are significantly elevated in the asthmatic airways 22,26,27 . As shown here, the inhibition of TSLP or its key signalling molecule, STAT5, can restore the sensitivity of NH cells to corticosteroids.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have revealed the involvement of TSLP in the patients with severe asthma as well as mouse asthma models 22,26,27 . Indeed, levels of Tslp mRNA and TSLP protein are elevated in the lungs of OVA alone or OVA þ IL-33 model mice ( Supplementary Fig.…”

Section: Tslp Is Associated With Corticosteroid Resistance In Vivomentioning

confidence: 99%

“…We identify thymic stromal lymphopoietin (TSLP), which is highly expressed in the bronchial epithelium of the patients with severe asthma 22 , as a key cytokine that induces corticosteroid resistance in NH cells in vitro and in vivo, and demonstrate that blockade of TSLP or its signalling through STAT5 can restore corticosteroid sensitivity.…”

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confidence: 99%

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Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

et al. 2013

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Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NHcell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Tslp Is Associated With Corticosteroid Resistance In Vivomentioning

confidence: 99%

mentioning

confidence: 99%

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Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

et al. 2013

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“…Human lung ILC2s were first identified by flow cytometry as Lin 2 CD127 þ CRTH2 þ and Lin 2 CD127 þ CD25 þ IL-33R þ cells in healthy fetal and adult lung tissue (Mjosberg et al 2011;Monticelli et al 2011), and were subsequently visualized by immunofluorescence as Lin 2 cKit þ CD161 þ cells (Barnig et al 2013). Elevated expression of IL-25, IL-33, and TSLP has been shown in human asthmatic lung tissue (Prefontaine et al 2010; Corrigan et al 2011;Shikotra et al 2012), and human peripheral blood ILC2s responded to asthma-associated PGD 2 by producing IL-13 (Barnig et al 2013). In addition, pathogenic LTD 4 -initiated lung ILC2 responses in mice were abrogated following treatment with montelukast ).…”

Section: Ilc2s and Allergic Airway Inflammationmentioning

confidence: 99%

Group 2 Innate Lymphoid Cells in Health and Disease

Kim

Artis

2015

Cold Spring Harb Perspect Biol

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Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORa, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell -derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems.

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Pharmacokinetics, Safety, and Tolerability of Tezepelumab (AMG 157) in Healthy and Atopic Dermatitis Adult Subjects

Parnes

Sullivan

Chen

et al. 2019

Clin Pharma and Therapeutics

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Tezepelumab (AMG 157) is a monoclonal antibody that targets thymic stromal lymphopoietin and has shown benefits in treating asthma. We assessed the safety, tolerability, and pharmacokinetics of single‐ascending and multiple‐ascending doses in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy and atopic dermatitis subjects were enrolled in the single‐dose study, and healthy subjects in the multiple‐dose study. Tezepelumab showed linear pharmacokinetics in both healthy and atopic dermatitis subjects. The half‐life after a subcutaneous or intravenous administration ranged from 19.9 to 25.7 days. After multiple doses, the mean area under the curve accumulation ratio was 1.82, 1.64, and 1.59 for the 35 mg, 105 mg, and 210 mg monthly subcutaneous doses, respectively. The mean maximum serum concentration (Cmax) accumulation ratio was 1.59, 2.84, and 6.74 for the 210 mg dose given every 28, 14, and 7 days, respectively. Tezepelumab was well tolerated in both studies with no evidence of immunogenicity.

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Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma

Cited by 283 publications

References 37 publications

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Group 2 Innate Lymphoid Cells in Health and Disease

Pharmacokinetics, Safety, and Tolerability of Tezepelumab (AMG 157) in Healthy and Atopic Dermatitis Adult Subjects

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