联合阻断 IL-6 和 TNF 对过敏性哮喘小鼠的治疗潜能
2022/05/17
摘要
联合抗细胞因子治疗是治疗未控制的激素抵抗型哮喘的一种有前途的方法。在这方面，最近，度普利尤单抗（抗IL-4Ra单克隆抗体）同时阻断IL-4和IL-13信号被批准用于严重嗜酸性哮喘。然而，目前尚无治疗中性粒细胞性哮喘的方法。我们对哮喘发病机制的最新研究表明，IL-6和TNF可能是治疗严重中性粒细胞性哮喘的潜在靶点。然而，同时抑制TNF和IL-6对哮喘的疗效尚未研究。为了评估联合细胞因子抑制的效力，我们同时向HDM诱导的哮喘的BALB/c小鼠予以IL-6和TNF抑制剂。IL-6/TNF联合抑制，而不是单独阻断这两种细胞因子，导致复杂的抗炎作用，包括减少Th2诱导的嗜酸性粒细胞增多，以及减少Th17/Th1介导的气道中性粒细胞浸润。综上所述，我们的结果为IL-6/TNF联合抑制治疗重度激素抵抗哮喘提供了证据。
Therapeutic Potential of Combining IL-6 and TNF Blockade in a Mouse Model of Allergic Asthma.
Olga A Namakanova, Ekaterina A Gorshkova
Abstrast
Combined anti-cytokine therapy is a promising therapeutic approach for uncontrolled steroid-resistant asthma. In this regard, simultaneous blockade of IL-4 and IL-13 signaling by Dupilumab (anti-IL-4Ra monoclonal antibody) was recently approved for severe eosinophilic asthma. However, no therapeutic options for neutrophilic asthma are currently available. Recent advances in our understanding of asthma pathogenesis suggest that both IL-6 and TNF may represent potential targets for treatment of severe neutrophilic asthma. Nevertheless, the efficacy of simultaneous pharmacological inhibition of TNF and IL-6 in asthma was not yet studied. To evaluate the potency of combined cytokine inhibition, we simultaneously administrated IL-6 and TNF inhibitors to BALB/c mice with HDM-induced asthma. Combined IL-6/TNF inhibition, but not individual blockade of these two cytokines, led to complex anti-inflammatory effects including reduced Th2-induced eosinophilia and less prominent Th17/Th1-mediated neutrophilic infiltrate in the airways. Taken together, our results provide evidence for therapeutic potential of combined IL-6/TNF inhibition in severe steroid-resistant asthma.
联合抗细胞因子治疗是治疗未控制的激素抵抗型哮喘的一种有前途的方法。在这方面，最近，度普利尤单抗（抗IL-4Ra单克隆抗体）同时阻断IL-4和IL-13信号被批准用于严重嗜酸性哮喘。然而，目前尚无治疗中性粒细胞性哮喘的方法。我们对哮喘发病机制的最新研究表明，IL-6和TNF可能是治疗严重中性粒细胞性哮喘的潜在靶点。然而，同时抑制TNF和IL-6对哮喘的疗效尚未研究。为了评估联合细胞因子抑制的效力，我们同时向HDM诱导的哮喘的BALB/c小鼠予以IL-6和TNF抑制剂。IL-6/TNF联合抑制，而不是单独阻断这两种细胞因子，导致复杂的抗炎作用，包括减少Th2诱导的嗜酸性粒细胞增多，以及减少Th17/Th1介导的气道中性粒细胞浸润。综上所述，我们的结果为IL-6/TNF联合抑制治疗重度激素抵抗哮喘提供了证据。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(International journal of molecular sciences 2022 Mar 24;23(7) doi:10.3390/ijms23073521)
(International journal of molecular sciences 2022 Mar 24;23(7) doi:10.3390/ijms23073521)
Therapeutic Potential of Combining IL-6 and TNF Blockade in a Mouse Model of Allergic Asthma.
Olga A Namakanova, Ekaterina A Gorshkova
Abstrast
Combined anti-cytokine therapy is a promising therapeutic approach for uncontrolled steroid-resistant asthma. In this regard, simultaneous blockade of IL-4 and IL-13 signaling by Dupilumab (anti-IL-4Ra monoclonal antibody) was recently approved for severe eosinophilic asthma. However, no therapeutic options for neutrophilic asthma are currently available. Recent advances in our understanding of asthma pathogenesis suggest that both IL-6 and TNF may represent potential targets for treatment of severe neutrophilic asthma. Nevertheless, the efficacy of simultaneous pharmacological inhibition of TNF and IL-6 in asthma was not yet studied. To evaluate the potency of combined cytokine inhibition, we simultaneously administrated IL-6 and TNF inhibitors to BALB/c mice with HDM-induced asthma. Combined IL-6/TNF inhibition, but not individual blockade of these two cytokines, led to complex anti-inflammatory effects including reduced Th2-induced eosinophilia and less prominent Th17/Th1-mediated neutrophilic infiltrate in the airways. Taken together, our results provide evidence for therapeutic potential of combined IL-6/TNF inhibition in severe steroid-resistant asthma.
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