IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease
IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease
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DOI：
10.1038/s41590-019-0467-1
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发表时间：
2019-09-01
影响因子：
30.5
通讯作者：
Dinarello, Charles A.
中科院分区：
文献类型：
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作者：
Hojen, Jesper Falkesgaard;Kristensen, Marie Louise Vindvad;Dinarello, Charles A.
白细胞介素 (IL)-1R3 是涉及 IL-1 家族六种细胞因子（IL-1 α、IL-1 β、IL-33、IL-36 α、IL-36 β 和 IL-36 γ）的三个信号传导途径的共受体。在许多疾病中，多种细胞因子有助于疾病的发病机制。例如，对于哮喘，IL-33 和 IL-1 都非常重要，IL-36 和 IL-1 对于牛皮癣也非常重要。我们开发了一种针对人 IL-1R3 (MAB-hR3) 的阻断单克隆抗体 (mAb)，并在此证明该抗体在体外特异性抑制通过 IL-1、IL-33 和 IL-36 的信号传导。此外，在三种不同的体内疾病模型（晶体诱导的腹膜炎、过敏性气道炎症和牛皮癣）中，我们发现用针对小鼠 IL-1R3 的单克隆抗体 (MAB-mR3) 靶向 IL-1R3 可显着减轻异质细胞因子驱动的炎症和疾病严重程度。我们的结论是，在由多种细胞因子驱动的疾病中，单一拮抗剂（例如 IL-1R3 的 mAb）是一种具有相当大转化益处的治疗选择。
Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1 alpha, IL-1 beta, IL-33, IL-36 alpha, IL-36 beta and IL-36 gamma). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.