Kageyama Kiyoto, Kikuchi Eri, Hoshino Nao
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Front Pharmacol. 2025 Mar 19;16:1546785. doi: 10.3389/fphar.2025.1546785. eCollection 2025.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and intractable chronic disease. Glucocorticoids are the mainstay of treatment for EGPA. The drugs that target interleukin (IL)-5 signaling have also been marketed or developed in recent years. While no animal model can completely recapitulate EGPA, the ovalbumin (OVA)-induced eosinophilic vasculitis mouse model exhibits pathological similarities in the lungs. However, the effect of an anti-IL-5 drug has not yet been investigated using this model. This study used the OVA-induced eosinophilic vasculitis model to evaluate and characterize its usefulness, focusing on the effects of an anti-IL-5 antibody.
Female C57BL/6NCrSlc mice were intraperitoneally immunized on days 0 and 14 with OVA adsorbed onto an aluminum gel. From days 26-32, the mice were exposed to aerosolized 1% OVA daily for 1 h. Anti-IL-5 antibody or vehicle was injected intravenously or intraperitoneally once on the first day of aerosol exposure (day 26). On day 33, the eosinophil and lymphocyte counts in the blood and bronchoalveolar lavage fluid (BALF) were measured. Lung specimens were used to assess the vascular lesions formed in the pulmonary arteries. Plasma cytokine levels were measured on day 28.
The anti-IL-5 antibody significantly reduced eosinophil counts in the blood and BALF. In contrast, it did not inhibit the lymphocyte counts in BALF or vascular lesion formation. The anti-IL-5 antibody significantly blocked the plasma level of IL-5 on day 28. However, the levels of other cytokines (i.e., IL-2, IL-6, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-12, IL-4, IL-13, and IL-17) were not altered.
In the investigated model, lymphocyte infiltration in lung tissue and cytokines other than or in addition to IL-5 were suggested to have contributed to the development of vasculitis. IL-5 signaling has a potential impact on EGPA pathogenesis via a different mechanism or in addition to the mechanism demonstrated in the OVA-induced eosinophilic vasculitis mouse model. The model may be useful for drug discovery targeting both eosinophilic and non-eosinophilic aspects of EGPA pathogenesis.
嗜酸性肉芽肿性多血管炎（EGPA）是一种罕见且难治的慢性疾病。糖皮质激素是EGPA治疗的主要药物。近年来，靶向白细胞介素（IL）-5信号通路的药物也已上市或正在研发。虽然没有动物模型能够完全重现EGPA，但卵清蛋白（OVA）诱导的嗜酸性血管炎小鼠模型在肺部表现出病理相似性。然而，尚未使用该模型研究抗IL-5药物的效果。本研究使用OVA诱导的嗜酸性血管炎模型来评估和表征其效用，重点关注抗IL-5抗体的作用。
雌性C57BL/6NCrSlc小鼠在第0天和第14天腹腔注射吸附在铝凝胶上的OVA进行免疫。从第26天至第32天，小鼠每天暴露于雾化的1%OVA中1小时。在雾化暴露的第一天（第26天），静脉或腹腔注射一次抗IL-5抗体或赋形剂。在第33天，测量血液和支气管肺泡灌洗液（BALF）中的嗜酸性粒细胞和淋巴细胞计数。使用肺标本评估肺动脉中形成的血管病变。在第28天测量血浆细胞因子水平。
抗IL-5抗体显著降低了血液和BALF中的嗜酸性粒细胞计数。相比之下，它并未抑制BALF中的淋巴细胞计数或血管病变形成。抗IL-5抗体在第28天显著阻断了血浆中IL-5的水平。然而，其他细胞因子（即IL-2、IL-6、肿瘤坏死因子-α、粒细胞-巨噬细胞集落刺激因子、干扰素-γ、IL-12、IL-4、IL-13和IL-17）的水平并未改变。
在所研究的模型中，提示肺组织中的淋巴细胞浸润以及除IL-5之外或与之相关的细胞因子促成了血管炎的发展。IL-5信号通路可能通过不同机制或除OVA诱导的嗜酸性血管炎小鼠模型中所证明的机制之外，对EGPA发病机制产生潜在影响。该模型可能有助于针对EGPA发病机制中嗜酸性和非嗜酸性方面的药物研发。
