Elimination of eosinophils using anti-IL-5 receptor alpha antibodies effectively suppresses IL-33-mediated pulmonary arterial hypertrophy
Elimination of eosinophils using anti-IL-5 receptor alpha antibodies effectively suppresses IL-33-mediated pulmonary arterial hypertrophy
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DOI：
10.1016/j.imbio.2017.12.002
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发表时间：
2018-06-01
期刊：
影响因子：
2.8
通讯作者：
Takatsu, Kiyoshi
中科院分区：
文献类型：
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作者：
Ikutani, Masashi;Ogawa, Shinya;Takatsu, Kiyoshi
白细胞介素 (IL)-5 是嗜酸性粒细胞的重要调节剂，也是哮喘的治疗靶点。过敏动物模型研究以及人体临床试验表明，施用抗 IL-5 或抗 IL-5 受体 (IL-5R) 抗体可以减少嗜酸性粒细胞计数并改善哮喘症状。为了探索 IL-5R 抗体的其他潜在临床用途，我们使用了 IL-33 介导的肺动脉肥大的动物模型。我们首先生成了针对小鼠 IL-5 受体 a 链 (IL-5R α) 的嵌合单克隆抗体，其中包含来自人 IgG1 的 Fc 区和来自先前建立的抗小鼠 IL-5R α 单克隆抗体的 Fab 区。为了研究抗体依赖性细胞介导的细胞毒性（ADCC）的作用，制备了缺乏 ADCC 的嵌合抗体。这些抗体识别 IL-5R α 的程度与 ADCC 充足的抗体相同。施用具有 ADCC 的嵌合抗体导致肺中嗜酸性粒细胞的消除，从而抑制动脉肥大的发展。在用缺乏 ADCC 的抗体治疗的小鼠中，这种效应减弱。总而言之，这项研究的结果为抗 IL-5R α 抗体在治疗导致肺动脉高压的动脉肥大中提供了潜在用途。
Interleukin (IL)-5 is a critical regulator of eosinophils and a therapeutic target for asthma. The administration of anti-IL-5 or anti-IL-5 receptor (IL-5R) antibodies has been shown to reduce eosinophil counts and ameliorate asthmatic symptoms in studies on animal models of allergy as well as in human clinical trials. In order to explore other potential clinical uses of IL-5R antibodies, we used an animal model of IL-33-mediated pulmonary arterial hypertrophy. We first generated chimeric monoclonal antibodies against the mouse IL-5 receptor a chain (IL-5R alpha), which comprised an Fc region from human IgG1 and a Fab region from a previously established anti mouse IL-5R alpha monoclonal antibody. To investigate the role of antibody-dependent cell-mediated cytotoxicity (ADCC), chimeric antibodies that lacked ADCC were prepared. These antibodies recognized IL-5R alpha to the same extent as the ADCC-suffIcient antibodies. Administration of chimeric antibodies with ADCC resulted in the elimination of eosinophils from the lung and thus suppressed the development of arterial hypertrophy. This effect was attenuated in mice treated with antibodies lacking ADCC. Taken together, the results of this study provided a potential use for anti-IL-5R alpha antibodies in the treatment of arterial hypertrophy, which leads to pulmonary hypertension.