MECHANISM OF PATHOGENESIS OF LATE-PHASE ASTHMATIC RESPONSE (LAR) : PREVENTIVE EFFECT OF ANTI-IL-5 ANTIBODY ON LAR IN ANIMAL MODEL

白细胞介素5（IL-5）通过与其受体（IL-5 R）相互作用诱导嗜酸性粒细胞的增殖和分化，所述受体由两个不同的多肽链α和β（betac）组成。单独的IL-5 Ra以低亲和力结合IL-5。本课题采用局部过敏原（气道）致敏动物模型，研究抗IL-5单克隆抗体对嗜酸性粒细胞向炎症区域浸润的影响，抗原诱导的迟发性哮喘反应（LAR）的发展和LAR后支气管反应性的增加。豚鼠暴露于雾化卵清蛋白（在雾化OVA激发后24小时，气管壁中嗜酸性粒细胞的数量增加。此外，所有动物都出现了明显的LAR，这是由呼吸阻力增加两倍的反应确定的，并在OVA激发后24小时表现出支气管对乙酰胆碱的反应性增加。然而，在用抗IL-5 mAb处理的动物中，与用对照抗体处理的动物相比，气管壁中的嗜酸性粒细胞数量显著减少。抗IL-5单克隆抗体治疗也显著抑制LAR的发展，尽管观察到类似的即刻支气管收缩幅度。此外，在抗IL-5抗体处理的豚鼠中，支气管对乙酰胆碱的反应性的增加显著降低。这些数据表明，IL-5参与气道嗜酸性粒细胞增多，LAR的发展和气道过敏原致敏诱导的支气管反应性增加。IL-5合成抑制剂和/或受体拮抗剂的开发可提供另一类治疗性抗哮喘药物。

Interleukin 5 (IL-5) induces proliferation and differentiation of eosinophils by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, alpha and beta (betac). The IL-5Ralpha alone binds IL-5 with low affinity. The betac does not bind IL-5 by itself, but does form a high affinity IL-5R in combination with IL-5Ralpha.In this project, an animal model of local allergen (airways) sensitization was employed to study the effects of anti-IL-5 mAb on infiltration of eosinophils into inflammatory region, the development of antigen-induced late asthmatic response (LAR) and the increased bronchial responsiveness following LAR.Guinea pigs exposed aerosolized ovalbumin (OVA) daily for 10 days developed increase in the number of eosinophils in the tracheal wall 24 hr after aerosolized OVA challenge. Furthermore, all animals developed apparent LAR determined by the response with a two-fold increase in respiratory resistance and showed an increase in bronchial responsiveness to acetycholine 24 hr after OVA challenge. In animals treated with anti-IL-5 mAb, however, eosinophil number in the tracheal wall dramatically decreased compared with animals treated with control antibody. The development of LAR was also remarkably suppressed by anti-IL-5 mAb treatment, although similar magnitude of immediate bronchoconstriction was observed. Moreover, in anti-IL-5 antibody treated guinea pigs, an increase in bronchial responsiveness to acetylcholine significantly decreased. The data demonstrate that IL-5 is involved in airway eosinophilia, development of LAR and an increase in bronchial responsiveness induced by allergen sensitization via the airways. Development of IL-5 synthesis inhibitors and/or receptor antagonists could provide another therapeutic class of anti-asthmatic drugs.