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Pharmacological inhibition of MutT homolog 1 (MTH1) in allergic airway inflammation as a novel treatment strategy

Adler, Anna LU ; Bergwik, Jesper LU ; Padra, Médea LU ; Papareddy, Praveen LU orcid ; Schmidt, Tobias LU ; Dahlgren, Madelene LU orcid ; Kahn, Robin LU ; Berglund, Ulrika Warpman and Egesten, Arne LU (2025) In Respiratory Research 26(1).
Abstract

Background: Despite progress in the treatment of asthma, there is an unmet need for additional therapeutic strategies, not least to avoid side-effects of corticosteroids. The enzyme MutT homolog 1 (MTH1) hydrolyzes oxidized purines and prevents their insertion to DNA. Small molecule inhibition of MTH1 has shown promising therapeutic effects in both cancer and inflammatory conditions. In this study, a small molecule inhibitor of MTH1 (TH1579), was investigated in models of allergic inflammation. Methods: In vitro, effects on T cell proliferation and apoptosis were investigated. Furthermore, a murine model, using female BALB/c mice, of OVA-induced allergic airway inflammation was used to investigate effects from MTH1-inhibition in vivo.... (More)

Background: Despite progress in the treatment of asthma, there is an unmet need for additional therapeutic strategies, not least to avoid side-effects of corticosteroids. The enzyme MutT homolog 1 (MTH1) hydrolyzes oxidized purines and prevents their insertion to DNA. Small molecule inhibition of MTH1 has shown promising therapeutic effects in both cancer and inflammatory conditions. In this study, a small molecule inhibitor of MTH1 (TH1579), was investigated in models of allergic inflammation. Methods: In vitro, effects on T cell proliferation and apoptosis were investigated. Furthermore, a murine model, using female BALB/c mice, of OVA-induced allergic airway inflammation was used to investigate effects from MTH1-inhibition in vivo. Results: Inhibition of MTH1 prevented T cell proliferation in vitro and induced apoptosis in isolated human CD4+ T cells. However, the viability of isolated human eosinophils was unaffected by MTH1 inhibition in vitro. Pharmacological inhibition of MTH1 in a murine model of allergic airway inflammation reduced mucus production, recruitment of inflammatory cells, such as T cells and eosinophils in the BAL fluid and lung tissue, reduced plasma levels of total IgE and OVA-specific IgE, IgG, and IgG1, as well as reduced IL-13 levels in BAL fluid, lung tissue and plasma. Conclusion: MTH1 inhibition reduced proliferation and promoted apoptosis of T cells in vitro. In vivo, TH1579 dampened the type 2 associated immune response in a murine model. These findings suggest that MTH1 could serve as a novel target to treat allergic airway inflammation.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Asthma, MTH1, T cells, TH1579, Type 2 inflammation
in
Respiratory Research
volume
26
issue
1
article number
101
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40087604
  • scopus:105000120377
ISSN
1465-9921
DOI
10.1186/s12931-025-03175-z
language
English
LU publication?
yes
id
2f995e56-7c05-4cd9-ad4b-750b2796c8f1
date added to LUP
2026-01-12 15:18:18
date last changed
2026-01-13 03:02:46
@article{2f995e56-7c05-4cd9-ad4b-750b2796c8f1,
  abstract     = {{<p>Background: Despite progress in the treatment of asthma, there is an unmet need for additional therapeutic strategies, not least to avoid side-effects of corticosteroids. The enzyme MutT homolog 1 (MTH1) hydrolyzes oxidized purines and prevents their insertion to DNA. Small molecule inhibition of MTH1 has shown promising therapeutic effects in both cancer and inflammatory conditions. In this study, a small molecule inhibitor of MTH1 (TH1579), was investigated in models of allergic inflammation. Methods: In vitro, effects on T cell proliferation and apoptosis were investigated. Furthermore, a murine model, using female BALB/c mice, of OVA-induced allergic airway inflammation was used to investigate effects from MTH1-inhibition in vivo. Results: Inhibition of MTH1 prevented T cell proliferation in vitro and induced apoptosis in isolated human CD4<sup>+</sup> T cells. However, the viability of isolated human eosinophils was unaffected by MTH1 inhibition in vitro. Pharmacological inhibition of MTH1 in a murine model of allergic airway inflammation reduced mucus production, recruitment of inflammatory cells, such as T cells and eosinophils in the BAL fluid and lung tissue, reduced plasma levels of total IgE and OVA-specific IgE, IgG, and IgG1, as well as reduced IL-13 levels in BAL fluid, lung tissue and plasma. Conclusion: MTH1 inhibition reduced proliferation and promoted apoptosis of T cells in vitro. In vivo, TH1579 dampened the type 2 associated immune response in a murine model. These findings suggest that MTH1 could serve as a novel target to treat allergic airway inflammation.</p>}},
  author       = {{Adler, Anna and Bergwik, Jesper and Padra, Médea and Papareddy, Praveen and Schmidt, Tobias and Dahlgren, Madelene and Kahn, Robin and Berglund, Ulrika Warpman and Egesten, Arne}},
  issn         = {{1465-9921}},
  keywords     = {{Asthma; MTH1; T cells; TH1579; Type 2 inflammation}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Respiratory Research}},
  title        = {{Pharmacological inhibition of MutT homolog 1 (MTH1) in allergic airway inflammation as a novel treatment strategy}},
  url          = {{http://dx.doi.org/10.1186/s12931-025-03175-z}},
  doi          = {{10.1186/s12931-025-03175-z}},
  volume       = {{26}},
  year         = {{2025}},
}