Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Immunology. 2022 Oct;167(2):197-211. doi: 10.1111/imm.13528. Epub 2022 Jul 12.
Type 2-high asthma is a chronic inflammatory disease of the airways which is increasingly prevalent in countries where helminth parasite infections are rare, and characterized by T helper 2 (Th2)-dependent accumulation of eosinophils in the lungs. Regulatory cytokines such as TGF-β can restrain inflammatory reactions, dampen allergic Th2 responses, and control eosinophil activation. The murine helminth parasite Heligmosomoides polygyrus releases a TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β despite bearing no structural similarity to the mammalian protein. Here, we investigated if Hp-TGM could alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen, house dust mite (HDM) extract or alum-adjuvanted ovalbumin protein (OVA). Intranasal administration of Hp-TGM during Alternaria exposure sharply reduced airway and lung tissue eosinophilia along with bronchoalveolar lavage fluid IL-5 and lung IL-33 cytokine levels at 24 h. The protective effect of Hp-TGM on airway eosinophilia was also obtained in the longer T-cell mediated models of HDM or OVA sensitisation with significant inhibition of eotaxin-1, IL-4 and IL-13 responses depending on the model and time-point. Hp-TGM was also protective when administered parenterally either when given at the time of allergic sensitisation or during airway allergen challenge. This project has taken the first steps in identifying the role of Hp-TGM in allergic asthma and highlighted its ability to control lung inflammation and allergic pathology. Future research will investigate the mode of action of Hp-TGM against airway allergic eosinophilia, and further explore its potential to be developed as a biotherapeutic in allergic asthma.
2 型高反应性哮喘是一种气道慢性炎症性疾病,在寄生虫感染罕见的国家中越来越普遍,其特征是肺部 Th2 细胞依赖性嗜酸性粒细胞积聚。调节性细胞因子,如 TGF-β,可抑制炎症反应,抑制过敏性 Th2 反应,并控制嗜酸性粒细胞的激活。鼠类寄生虫 Heligmosomoides polygyrus 释放一种 TGF-β模拟物(Hp-TGM),尽管与哺乳动物蛋白没有结构相似性,但具有 TGF-β的生物学和功能特性。在这里,我们研究了 Hp-TGM 是否可以减轻暴露于Alternaria alternata 过敏原、屋尘螨(HDM)提取物或铝佐剂卵清蛋白(OVA)的小鼠中的过敏性气道炎症。在 Alternaria 暴露期间鼻内给予 Hp-TGM,可显著降低气道和肺组织嗜酸性粒细胞浸润,以及支气管肺泡灌洗液中的 IL-5 和肺中的 IL-33 细胞因子水平,在 24 小时时达到高峰。在更长的 T 细胞介导的 HDM 或 OVA 致敏模型中,Hp-TGM 对气道嗜酸性粒细胞增多也具有保护作用,根据模型和时间点,显著抑制 eotaxin-1、IL-4 和 IL-13 反应。当在过敏致敏时或在气道过敏原挑战时给予 Hp-TGM 时,其也具有保护作用。该项目首次确定了 Hp-TGM 在过敏性哮喘中的作用,并强调了其控制肺部炎症和过敏性病理的能力。未来的研究将研究 Hp-TGM 对抗气道过敏性嗜酸性粒细胞增多的作用机制,并进一步探索其作为过敏性哮喘生物治疗的潜力。