通过颠覆局部免疫环境，肺部活结核疫苗对已建立的哮喘的治疗效果。
Therapeutic efficacy of pulmonary live tuberculosis vaccines against established asthma by subverting local immune environment.
机构信息
Grupo de Genética de Micobacterias, Dpto. Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, ISS Aragón, C/ Domingo Miral s/n, Zaragoza 50009, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid 28029, Spain.
Grupo de Genética de Micobacterias, Dpto. Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, ISS Aragón, C/ Domingo Miral s/n, Zaragoza 50009, Spain; CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid 28029, Spain; Servicio de Microbiología, Hospital Universitario Miguel Servet, ISS Aragón, Paseo Isabel la Católica 1-3, Zaragoza 50009, Spain.
出版信息
EBioMedicine. 2021 Feb;64:103186. doi: 10.1016/j.ebiom.2020.103186. Epub 2021 Jan 18.
BACKGROUND
Substantial recent advances in the comprehension of the molecular and cellular mechanisms behind asthma have evidenced the importance of the lung immune environment for disease outcome, making modulation of local immune responses an attractive therapeutic target against this pathology. Live attenuated mycobacteria, such as the tuberculosis vaccine BCG, have been classically linked with a type 1 response, and proposed as possible modulators of the type 2 response usually associated with asthma.
METHODS
In this study we used different acute and chronic murine models of asthma to investigate the therapeutic efficacy of intranasal delivery of the live tuberculosis vaccines BCG and MTBVAC by regulating the lung immune environment associated with airway hyperresponsiveness (AHR).
FINDINGS
Intranasal administration of BCG, or the novel tuberculosis vaccine candidate MTBVAC, abrogated AHR-associated hallmarks, including eosinophilia and lung remodeling. This correlated with the re-polarization of allergen-induced M2 macrophages towards an M1 phenotype, as well as with the induction of a strong allergen-specific Th1 response. Importantly, vaccine treatment was effective in a scenario of established chronic asthma where a strong eosinophil infiltration was already present prior to immunization. We finally compared the nebulization efficiency of clinical formulations of MTBVAC and BCG using a standard commercial nebulizer for potential aerosol application.
INTERPRETATION
Our results demonstrate that pulmonary live tuberculosis vaccines efficiently revert established asthma in mice. These data support the further exploration of this approach as potential therapy against asthma.
FUNDING
Spanish Ministry of Science [grant numbers: BIO2014-5258P, RTI2018-097625-B-I00], Instituto de Salud Carlos III, Gobierno de Aragón/Fondo Social Europeo, University of Zaragoza [grant number: JIUZ-2018-BIO-01].
背景
近年来，人们对哮喘背后的分子和细胞机制的理解有了实质性的进展，这表明肺部免疫环境对疾病结局的重要性，使得调节局部免疫反应成为针对这种病理的一种有吸引力的治疗靶点。减毒活分枝杆菌，如结核疫苗 BCG，通常与 1 型反应有关，并被提议作为与哮喘相关的 2 型反应的可能调节剂。
方法
在这项研究中，我们使用了不同的急性和慢性哮喘小鼠模型，通过调节与气道高反应性（AHR）相关的肺部免疫环境，来研究鼻内给予活结核疫苗 BCG 和 MTBVAC 的治疗效果。
发现
BCG 或新型结核候选疫苗 MTBVAC 的鼻内给药消除了与 AHR 相关的特征，包括嗜酸性粒细胞增多和肺重塑。这与过敏原诱导的 M2 巨噬细胞向 M1 表型的重新极化以及强烈的过敏原特异性 Th1 反应的诱导有关。重要的是，疫苗治疗在已建立的慢性哮喘中是有效的，在免疫之前已经存在强烈的嗜酸性粒细胞浸润。我们最后使用标准商业雾化器比较了 MTBVAC 和 BCG 的临床制剂的雾化效率，以用于潜在的气溶胶应用。
解释
我们的结果表明，肺部活结核疫苗可有效逆转小鼠的已建立的哮喘。这些数据支持进一步探索这种方法作为治疗哮喘的潜在疗法。
资金
西班牙科学部[资助编号：BIO2014-5258P、RTI2018-097625-B-I00]、西班牙卡洛斯三世健康研究所、阿拉贡政府/欧洲社会基金、萨拉戈萨大学[资助编号：JIUZ-2018-BIO-01]。
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