Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma
Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma
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DOI：
10.4049/jimmunol.164.10.5409
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发表时间：
2000-05-15
影响因子：
4.4
通讯作者：
Monia, BP
中科院分区：
文献类型：
--
作者：
Karras, JG;McGraw, K;Monia, BP
慢性气道嗜酸性粒细胞增多症与变应性哮喘相关，并且部分由变应原特异性Th 2淋巴细胞分泌的IL-5介导。IL-5是已知的嗜酸性粒细胞的成熟和抗凋亡因子，并刺激新生嗜酸性粒细胞从骨髓释放到外周循环中。在体外发现特异性抑制IL-5表达的反义寡核苷酸在小鼠OVA肺激发和过敏性腹膜炎模型中均观察到显著减少实验诱导的体内嗜酸性粒细胞增多症。静脉给药导致嗜酸性粒细胞增多症的序列依赖性抑制与IL-5蛋白水平的降低一致，支持反义作用机制。在停止寡核苷酸给药后长达17天观察到肺嗜酸性粒细胞增多症的有效抑制，表明该策略实现了长期保护。此外，还观察到序列特异性的、反义寡核苷酸介导的对Ag介导的晚期气道高反应性的抑制。这些数据强调了靶向IL-5的反义方法用于治疗哮喘和嗜酸性粒细胞疾病的潜在效用。
Chronic airway eosinophilia is associated with allergic asthma and is mediated in part by secretion of IL-5 from allergen-specific Th2 lymphocytes, IL-5 is a known maturation and antiapoptotic factor for eosinophils and stimulates release of nascent eosinophils from bone marrow into the peripheral circulation. An antisense oligonucleotide found to specifically inhibit IL-5 expression in vitro was observed to significantly reduce experimentally induced eosinophilia in vivo, in both the murine OVA lung challenge and allergic peritonitis models. Intravenous administration resulted in sequence-dependent inhibition of eosinophilia coincident with reduction of IL-5 protein levels, supporting an antisense mechanism of action. Potent suppression of lung eosinophilia was observed up to 17 days after cessation of oligonucleotide dosing, indicating achievement of prolonged protection with this strategy. Furthermore, sequence-specific, antisense oligonucleotide-mediated inhibition of Ag-mediated late phase airway hyperresponsiveness was also observed. These data underscore the potential utility of an antisense approach targeting IL-5 for the treatment of asthma and eosinophilic diseases.