Adler Anna, Bergwik Jesper, Padra Médea, Papareddy Praveen, Schmidt Tobias, Dahlgren Madelene, Kahn Robin, Berglund Ulrika Warpman, Egesten Arne
Division of Respiratory Medicine, Allergology, & Palliative Medicine, Department of Clinical Sciences Lund and Skåne University Hospital, Lund, Sweden.
Department of Laboratory Medicine, Lund University, Lund, Sweden.
Respir Res. 2025 Mar 14;26(1):101. doi: 10.1186/s12931-025-03175-z.
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.
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.
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.
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.
尽管哮喘治疗取得了进展，但仍需要更多的治疗策略，尤其是要避免皮质类固醇的副作用。MutT同源蛋白1（MTH1）酶可水解氧化嘌呤并阻止其插入DNA。MTH1的小分子抑制在癌症和炎症性疾病中均显示出有前景的治疗效果。在本研究中，对MTH1的小分子抑制剂（TH1579）在变应性炎症模型中进行了研究。
在体外，研究其对T细胞增殖和凋亡的影响。此外，使用雌性BALB/c小鼠建立卵清蛋白（OVA）诱导的变应性气道炎症小鼠模型，以研究体内MTH1抑制的作用。
抑制MTH1可在体外阻止T细胞增殖，并诱导分离的人CD4 T细胞凋亡。然而，分离的人嗜酸性粒细胞的活力在体外不受MTH1抑制的影响。在变应性气道炎症小鼠模型中对MTH1进行药理抑制可减少黏液分泌，减少炎症细胞（如BAL液和肺组织中的T细胞和嗜酸性粒细胞）的募集，降低血浆中总IgE和OVA特异性IgE、IgG及IgG1的水平，以及降低BAL液、肺组织和血浆中的IL-13水平。
抑制MTH1可在体外减少T细胞增殖并促进其凋亡。在体内，TH1579可减轻小鼠模型中2型相关免疫反应。这些发现表明，MTH1可作为治疗变应性气道炎症的新靶点。
