Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Mass; Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Boston Children's Hospital, Harvard Medical School, Boston, Mass.
J Allergy Clin Immunol. 2019 Jul;144(1):94-108.e11. doi: 10.1016/j.jaci.2018.12.1022. Epub 2019 Jan 29.
Allergic asthma causes morbidity in many subjects, and novel precision-directed treatments would be valuable.
We sought to examine the role of a novel innate molecule, repulsive guidance molecule b (RGMb), in murine models of allergic asthma.
In models of allergic asthma using ovalbumin or cockroach allergen, mice were treated with anti-RGMb or control mAb and examined for airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. The mechanisms by which RGMb causes airways disease were also examined.
We found that blockade of RGMb by treatment with anti-RGMb mAb effectively blocked the development of airway inflammation and AHR. Importantly, blockade of RGMb completely blocked the development of airway inflammation and AHR, even if treatment occurred only during the challenge (effector) phase. IL-25 played an important role in these models of asthma because IL-25 receptor-deficient mice did not develop disease after sensitization and challenge with allergen. RGMb was expressed primarily by innate cells in the lungs, including bronchial epithelial cells (known producers of IL-25), activated eosinophils, and interstitial macrophages, which in the inflamed lung expressed the IL-25 receptor and produced IL-5 and IL-13. We also found that neogenin, the canonical receptor for RGMb, was expressed by interstitial macrophages and bronchial epithelial cells in the inflamed lung, suggesting that an innate RGMb-neogenin axis might modulate allergic asthma.
These results demonstrate an important role for a novel innate pathway in regulating type 2 inflammation in patients with allergic asthma involving RGMb and RGMb-expressing cells, such as interstitial macrophages and bronchial epithelial cells. Moreover, targeting this previously unappreciated innate pathway might provide an important treatment option for allergic asthma.
过敏性哮喘会使许多患者发病，新型靶向精准治疗方法将具有重要价值。
我们旨在探究新型先天分子——排斥导向分子 b（RGMb）在过敏性哮喘的小鼠模型中的作用。
使用卵清蛋白或蟑螂过敏原建立过敏性哮喘模型，通过给予抗 RGMb 或对照 mAb 治疗，检测气道炎症和气道高反应性（AHR），这是哮喘的主要特征。还研究了 RGMb 导致气道疾病的机制。
我们发现，通过抗 RGMb mAb 阻断 RGMb 可有效抑制气道炎症和 AHR 的发展。重要的是，即使在挑战（效应）阶段仅进行治疗，阻断 RGMb 也可完全抑制气道炎症和 AHR 的发展。IL-25 在这些哮喘模型中起着重要作用，因为 IL-25 受体缺陷型小鼠在致敏和用过敏原激发后不会发病。RGMb 主要由肺部的先天细胞表达，包括支气管上皮细胞（已知的 IL-25 产生细胞）、活化的嗜酸性粒细胞和间质巨噬细胞，这些细胞在炎症肺中表达 IL-25 受体并产生 IL-5 和 IL-13。我们还发现，RGMb 的经典受体——神经导向因子受体 4（neogenin），在炎症肺中的间质巨噬细胞和支气管上皮细胞中表达，提示先天 RGMb-neogenin 轴可能调节过敏性哮喘。
这些结果表明，新型先天途径在调节过敏性哮喘患者的 2 型炎症中具有重要作用，涉及 RGMb 和表达 RGMb 的细胞，如间质巨噬细胞和支气管上皮细胞。此外，靶向这一先前未被重视的先天途径可能为过敏性哮喘提供重要的治疗选择。
