Kim Sung-Ryeol, Um Yun Jung, Chung Sook In, Jeong Kyoung Yong, Park Hye Jung, Park Kyung Hee, Park Jung-Won, Park Sang Gyu, Lee Jae-Hyun
Yongin Severance Hospital, Yonsei University College of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Kyounggi-do, Republic of Korea.
College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea.
World Allergy Organ J. 2024 Aug 22;17(9):100956. doi: 10.1016/j.waojou.2024.100956. eCollection 2024 Sep.
Several biologics have been developed and used to treat severe asthma. However, commercialized biologics have limitations in treating T2-low asthma because their main target is the T2 inflammation marker. Therefore, there is an unmet need for treating T2-low severe asthma. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is an auxiliary protein in the mammalian multi-aminoacyl-tRNA synthetase complex. AIMP1 also acts as a cytokine and induces the secretion of proinflammatory cytokines. Since anti-AIMP1 has been shown to reduce interleukin (IL)-6, tumor necrosis factor-α, and IL-17A levels in a mouse model, it could be effective in the treatment of T2-low severe asthma.
Wild-type BALB/c mice were sensitized and challenged with intranasal inoculation of a crude HDM extract. Atliximab, a chimeric AIMP1 antibody, was administered once (20 μg, 40 μg, 100 μg) on Day 14. We evaluated airway hyperresponsiveness (AHR), performed cellular analyses of the bronchoalveolar lavage fluid (BALF), measured inflammatory cytokine levels, and examined peribronchial histological features.
Atliximab reduced AIMP1 levels in asthmatic mice in a dose-dependent manner. AHR and Inflammatory cells such as neutrophils and eosinophils in the BALF decreased in asthmatic mice treated with atliximab. The levels of IL-6, IL-13, and transforming growth factor-β (TGF-β) in the lung tissue decreased in asthmatic mice treated with a high dose of atliximab (100 μg). Atliximab also reduced goblet cell hyperplasia and peribronchial fibrosis.
Atliximab improved asthmatic airway inflammation including neutrophilic inflammation in HDM-induced asthma mice. These data suggest that anti-AIMP1 plays an important role in the treatment of severe T2-low asthma.
已经开发了几种生物制剂并用于治疗重度哮喘。然而，商业化的生物制剂在治疗T2低型哮喘方面存在局限性，因为它们的主要靶点是T2炎症标志物。因此，治疗T2低型重度哮喘存在未满足的需求。氨酰基-tRNA合成酶相互作用多功能蛋白1（AIMP1）是哺乳动物多氨酰基-tRNA合成酶复合物中的一种辅助蛋白。AIMP1还作为一种细胞因子，诱导促炎细胞因子的分泌。由于抗AIMP1已被证明在小鼠模型中可降低白细胞介素（IL）-6、肿瘤坏死因子-α和IL-17A水平，因此它可能对治疗T2低型重度哮喘有效。
野生型BALB/c小鼠通过鼻内接种粗制屋尘螨提取物进行致敏和激发。在第14天，一次性给予阿特利昔单抗（一种嵌合AIMP1抗体，剂量分别为20μg、40μg、100μg）。我们评估了气道高反应性（AHR），对支气管肺泡灌洗液（BALF）进行了细胞分析，测量了炎症细胞因子水平，并检查了支气管周围的组织学特征。
阿特利昔单抗以剂量依赖的方式降低了哮喘小鼠体内的AIMP1水平。在用阿特利昔单抗治疗的哮喘小鼠中，AHR以及BALF中的中性粒细胞和嗜酸性粒细胞等炎症细胞减少。高剂量阿特利昔单抗（100μg）治疗的哮喘小鼠肺组织中IL-6、IL-13和转化生长因子-β（TGF-β）水平降低。阿特利昔单抗还减少了杯状细胞增生和支气管周围纤维化。
阿特利昔单抗改善了屋尘螨诱导的哮喘小鼠的哮喘气道炎症，包括嗜中性炎症。这些数据表明，抗AIMP1在重度T2低型哮喘的治疗中起重要作用。
