静脉注射活结核疫苗 MTBVAC 后，系统性过敏原脱敏与小鼠长期哮喘保护之间的相关性。
Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC.
机构信息
Grupo de Genética de Micobacterias, Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, IIS-Aragon, Zaragoza, Spain; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
出版信息
EBioMedicine. 2024 Sep;107:105272. doi: 10.1016/j.ebiom.2024.105272. Epub 2024 Aug 21.
BACKGROUND
MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs.
METHODS
Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens.
FINDINGS
IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5.
INTERPRETATION
Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure.
FUNDING
MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.
背景
MTBVAC 是一种减毒活结核疫苗，目前正在进行 III 期临床试验以预防结核病。在之前的临床前研究中，我们发现通过鼻腔途径局部肺部给予 MTBVAC 对哮喘具有很强的治疗作用。这种作用与肺部过敏原特异性 Th2 反应的消除有关。
方法
使用不同的哮喘小鼠模型，我们研究了通过静脉（IV）途径给予 MTBVAC 的效果及其作为免疫治疗剂在全身水平诱导过敏原特异性反应脱敏的潜力。我们探讨了这一过程在对抗暴露于不同过敏原引起的气道高反应性（AHR）中的效果。
结果
IV MTBVAC 非常有效地降低了不同过敏原引起的 AHR。此外，IV MTBVAC 被发现耐受性良好，从分析的不同器官中逐渐消除。从机制角度来看，我们观察到 MTBVAC 静脉内，而不是鼻内，可抑制肺部和脾脏中的过敏原特异性 Th2 反应。这种全身性降低与对过敏原暴露的长期治疗保护相关。我们的结果还揭示了调节全身和局部肺过敏原脱敏过程的不同免疫机制。值得注意的是，在一组对屋尘螨（HDM）敏感的哮喘患者中，外周血单核细胞（PBMC）与 MTBVAC 孵育可防止过敏原特异性产生 Th2 细胞因子 IL-4 和 IL-5。
解释
总的来说，我们的结果表明，静脉内 MTBVAC 可能是治疗哮喘的一种合理的过敏原脱敏方法，并可提供对过敏原暴露的长期保护。
资金
MCIN/AEI/10.13039/501100011033[授予号 RTI2018-097625-B-I00 和 PID2022-138624OB-I00]；Consorcio Centro de Investigación Biomédica en Red-（Groups CB06/06/0020 和 CB06/06/0013），Instituto de Salud Carlos III。
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