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

晚期哮喘反应（LAR）的发病机制：抗IL-5抗体对动物模型中LAR的预防作用

基本信息

批准号：
05557023
负责人：
TAKATSU Kiyoshi
金额：
$ 8.13万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

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.

白细胞介素5(IL-5)通过与其受体(IL-5R)相互作用而诱导嗜酸性粒细胞增殖和分化，IL-5R由两个不同的多肽链组成，即α和β(β)。IL-5Rpha单独以低亲和力与IL-5结合。Betac本身不与IL-5结合，但与IL-5α结合形成高亲和力的IL-5R。本项目采用局部过敏原(呼吸道)致敏的动物模型，研究抗IL-5单抗对嗜酸性粒细胞向炎症区域的渗透、抗原诱导的迟发性哮喘反应(LAR)的发生以及LAR后支气管反应性的增强的影响。豚鼠每天雾化卵白蛋白(OVA)10天后，气管壁嗜酸性粒细胞数量增加。此外，所有动物都出现了明显的LAR，呼吸阻力增加了两倍，并在OVA攻击后24小时显示出对乙酰胆碱的支气管反应性增加。然而，在抗IL-5单抗处理的动物中，与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单抗治疗也显著抑制了LAR的发展，尽管观察到了类似程度的即刻支气管收缩。此外，在抗IL-5抗体治疗的豚鼠中，对乙酰胆碱的支气管反应性增加显著降低。这些数据表明，IL-5参与了呼吸道嗜酸性粒细胞增多症、LAR的发生和过敏原致敏引起的支气管反应性的增加。IL-5合成抑制剂和/或受体拮抗剂的开发可能提供另一类治疗哮喘的药物。