Park Sang Chul, Kim Hongmin, Bak Yeeun, Shim Dahee, Kwon Kee Woong, Kim Chang Hoon, Yoon Joo Heon, Shin Sung Jae
Department of Otorhinolaryngology-Head and Neck surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
Allergy Asthma Immunol Res. 2020 May;12(3):537-555. doi: 10.4168/aair.2020.12.3.537.
Simple and reliable animal models of human diseases contribute to the understanding of disease pathogenesis as well as the development of therapeutic interventions. Although several murine models to mimic human asthma have been established, most of them require anesthesia, resulting in variability among test individuals, and do not mimic asthmatic responses accompanied by T-helper (Th) 17 and neutrophils. As dendritic cells (DCs) are known to play an important role in initiating and maintaining asthmatic inflammation, we developed an asthma model via adoptive transfer of allergen-loaded DCs.
Ovalbumin (OVA)-loaded bone marrow-derived DCs (BMDCs) (OVA-BMDCs) were injected intravenously 3 times into non-anesthetized C57BL/6 mice after intraperitoneal OVA-sensitization.
OVA-BMDC-transferred mice developed severe asthmatic immune responses when compared with mice receiving conventional OVA challenge intranasally. Notably, remarkable increases in systemic immunoglobulin (Ig) E and IgG1 responses, Th2/Th17-associated cytokines (interleukin [IL]-5, IL-13 and IL-17), Th2/Th17-skewed T-cell responses, and cellular components, including eosinophils, neutrophils, and goblet cells, were observed in the lungs of OVA-BMDC-transferred mice. Moreover, the asthmatic immune responses and severity of inflammation were correlated with the number of OVA-BMDCs transferred, indicating that the disease severity and asthma type may be adjusted according to the experimental purpose by this method. Furthermore, this model exhibited less variation among the test individuals than the conventional model. In addition, this DCs-based asthma model was partially resistant to steroid treatment.
A reliable murine model of asthma by intravenous (i.v.) transfer of OVA-BMDCs was successfully established without anesthesia. This model more accurately reflects heterogeneous human asthma, exhibiting a robust Th2/Th17-skewed response and eosinophilic/neutrophilic infiltration with good reproducibility and low variation among individuals. This model will be useful for understanding the pathogenesis of asthma and would serve as an alternative tool for immunological studies on the function of DCs, T-cell responses and new drugs.
简单可靠的人类疾病动物模型有助于理解疾病发病机制以及开发治疗干预措施。尽管已经建立了几种模拟人类哮喘的小鼠模型，但大多数模型需要麻醉，导致测试个体之间存在差异，并且不能模拟伴有辅助性T细胞（Th）17和中性粒细胞的哮喘反应。由于已知树突状细胞（DCs）在引发和维持哮喘炎症中起重要作用，我们通过过继转移负载变应原的DCs建立了一种哮喘模型。
在腹腔内卵清蛋白（OVA）致敏后，将负载OVA的骨髓来源DCs（BMDCs）（OVA-BMDCs）静脉内注射3次到未麻醉的C57BL/6小鼠体内。
与经鼻接受传统OVA激发的小鼠相比，OVA-BMDC转移的小鼠产生了严重的哮喘免疫反应。值得注意的是，在OVA-BMDC转移的小鼠肺中观察到全身免疫球蛋白（Ig）E和IgG1反应、Th2/Th17相关细胞因子（白细胞介素[IL]-5、IL-13和IL-17）、Th2/Th17偏向的T细胞反应以及包括嗜酸性粒细胞、中性粒细胞和杯状细胞在内的细胞成分显著增加。此外，哮喘免疫反应和炎症严重程度与转移的OVA-BMDC数量相关，表明通过该方法可根据实验目的调整疾病严重程度和哮喘类型。此外，该模型在测试个体之间的变异性比传统模型小。此外，这种基于DCs的哮喘模型对类固醇治疗部分耐药。
通过静脉内（i.v.）转移OVA-BMDC成功建立了一种无需麻醉的可靠小鼠哮喘模型。该模型更准确地反映了异质性人类哮喘，表现出强烈的Th2/Th17偏向反应和嗜酸性粒细胞/中性粒细胞浸润，具有良好的可重复性和个体间低变异性。该模型将有助于理解哮喘发病机制，并可作为DCs功能、T细胞反应和新药免疫研究的替代工具。
