Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2021 Aug;148(2):574-584.
doi: 10.1016/j.jaci.2021.05.043. Epub 2021 Jun 16.

Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease

Kathleen M Buchheit  1 , Erin Lewis  2 , Deborah Gakpo  2 , Jonathan Hacker  2 , Aaqib Sohail  1 , Faith Taliaferro  3 , Evans Berreondo Giron  4 , Chelsea Asare  4 , Marko Vukovic  5 , Jillian C Bensko  2 , Daniel F Dwyer  1 , Alex K Shalek  6 , Jose Ordovas-Montanes  7 , Tanya M Laidlaw  8
Affiliations
Clinical Trial

Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease

Kathleen M Buchheit et al. J Allergy Clin Immunol. 2021 Aug.

Abstract

Background: Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to antieosinophil effects.

Objective: We sought to identify the mechanisms by which anti-IL-5 treatment with mepolizumab improves respiratory inflammation in AERD.

Methods: The clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, and antibody levels, and urinary and nasal eicosanoid levels were measured for 18 subjects with AERD who were taking mepolizumab and compared with those of 18 matched subjects with AERD who were not taking mepolizumab.

Results: Subjects taking mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained had higher surface CRTH2 expression than did the cells from subjects not taking mepolizumab. Nasal prostaglandin F2α, prostaglandin D2 metabolites, leukotriene B4, and thromboxane levels were lower in subjects taking mepolizumab, as were urinary levels of tetranor-prostaglandin D2 and leukotriene E4. The nasal epithelial cell transcripts that were overexpressed among subjects with AERD who were taking mepolizumab were enriched for genes involved in tight junction formation and cilium organization. Nasal and urinary prostaglandin E2, tryptase, and antibody levels were not different between the 2 groups.

Conclusion: IL-5 inhibition in AERD decreases production of inflammatory eicosanoids and upregulates tight junction-associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contribute to the mechanism of benefit afforded by mepolizumab.

Keywords: Aspirin-exacerbated respiratory disease; CRTH2; IL-5; chronic rhinosinusitis; leukotriene; mepolizumab; nasal polyp; prostaglandin D(2); prostaglandin F(2α).

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: T Laidlaw has served on scientific advisory boards for GlaxoSmithKline and Sanofi-Genzyme, Optinose, and Regeneron. K Buchheit has served on scientific advisory boards for AstraZeneca and GlaxoSmithKline. J Bensko has served on scientific advisory boards for GlaxoSmithKline. J Ordovas-Montanes reports compensation for consulting services with Cellarity and Hovione. A Shalek reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Hovione, Third Rock Ventures, Ochre Bio, Relation Therapeutics, and Dahlia Biosciences. A Shalek has received research support from Merck, Novartis, Leo Pharma, Janssen, the Bill and Melinda Gates Foundation, the Moore Foundation, the Pew-Stewart Trust, Fondation MIT, the Chan Zuckerberg Initiative, Novo Nordisk and the FDA unrelated to this work. The rest of the authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.. Peripheral blood granulocyte levels and their CRTH2 expression in subjects on mepolizumab compared to controls.
Circulating eosinophil (A), basophil (B) and neutrophil (C) levels were measured by flow cytometry and expressed as a percentage of all CD45+ cells in AERD subjects treated (Mepolizumab) or not (Control) with mepolizumab. Surface CRTH2 expression of eosinophils (D) and basophils (E) was calculated for the same subjects, expressed as Median Fluorescence Intensity (MFI) of CRTH2 with isotype subtracted.
Figure 2.
Figure 2.. Nasal and urinary eicosanoid levels in subjects on mepolizumab compared to controls.
Nasal fluid levels of (A) DHKPGD2 (B) PGF2α + tetranor PGFM (C) TXB2 and (D) LTB4. Urinary levels of (E) tetranor PGDM and (F) LTE4.
Figure 3.
Figure 3.. Relationship of nasal eicosanoids to granulocyte expression of CRTH2 in subjects on mepolizumab and controls.
Correlation of nasal DHKPGD2 with surface CRTH2 expression of eosinophils (A) and basophils (B). Correlation of PGF2α + tetranor PGFM with surface CRTH2 expression of eosinophils (C) and basophils (D). Subjects treated with mepolizumab represented by red circles, controls represented by black circles.
Figure 4.
Figure 4.. IgE and IgG4 levels in subjects on mepolizumab compared to controls.
Serum (A-B) and nasal fluid (C-D) levels of IgE and IgG4 in AERD subjects treated (Mepolizumab, red circles) or not (Control, black circles) with mepolizumab.
Figure 5.
Figure 5.. Sinus tissue single-cell RNA-sequencing and hierarchical clustering analysis of nasal inferior turbinate scraping transcriptomic changes in mepolizumab-treated patients.
(A) T-stochastic neighbor embedding (t-SNE) plot of 18,036 surgically excised sinus tissue cells from subjects with AERD (n=3 samples), CRSwNP (n=3 samples), and CRS without nasal polyps (n=5 samples) colored by cell type (left) and IL5RA expression (right). (B) Unsupervised hierarchical clustering analysis of tight junction-related genes shows clustering of mepolizumab-treated subjects and untreated control subjects, with induction of tight junction related genes in mepolizumab-treated group (row-normalized gene expression values), P < 0.05 for all genes.
See this image and copyright information in PMC

References

    1. Bhattacharyya N Assessing the additional disease burden of polyps in chronic rhinosinusitis. Ann Otol Rhinol Laryngol. 2009;118(3):185–9. - PubMed
    1. Campbell AP, Phillips KM, Hoehle LP, Feng AL, Bergmark RW, Caradonna DS, et al. Depression symptoms and lost productivity in chronic rhinosinusitis. Ann Allergy Asthma Immunol. 2017;118(3):286–9. - PubMed
    1. McMains KC, Kountakis SE. Medical and surgical considerations in patients with Samter’s triad. American journal of rhinology. 2006;20(6):573–6. - PubMed
    1. Stevens WW, Ocampo CJ, Berdnikovs S, Sakashita M, Mahdavinia M, Suh L, et al. Cytokines in Chronic Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory Disease. Am J Respir Crit Care Med. 2015;192(6):682–94. - PMC - PubMed
    1. Laidlaw TM, Prussin C, Panettieri RA, Lee S, Ferguson BJ, Adappa ND, et al. Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size. Laryngoscope. 2019;129(2):E61–E6. - PubMed

Publication types

MeSH terms