Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.
Pieris Pharmaceuticals GmbH, Hallbergmoos, Germany.
Am J Physiol Lung Cell Mol Physiol. 2024 Nov 1;327(5):L624-L633. doi: 10.1152/ajplung.00295.2023. Epub 2024 Aug 6.
Severe asthma is a syndromic label assigned to patients based on clinical parameters, yet there are diverse underlying molecular endotypes in severe asthma pathobiology. Immunophenotyping of asthma biospecimens commonly includes a mixture of granulocytes and lymphocytes. Recently, a subset of patients with severe asthma was defined as non-type 2 with neutrophil-enriched inflammation associated with increased Th17 CD4 T cells and IL-17 levels. Here, we used an allergen-driven mouse model of increased IL-17 and mixed granulocyte lung inflammation to determine the impact of upstream regulation by an Anticalin protein that specifically binds IL-23. Airway administration of the IL-23-binding Anticalin protein (AcIL-23) decreased lung neutrophils, eosinophils, macrophages, lymphocytes, IL-17 CD4 T cells, mucous cell metaplasia, and methacholine-induced airway hyperresponsiveness. Selective targeting of IL-23 with a monoclonal antibody (IL-23p19; αIL-23) also decreased macrophages, IL-17 CD4 T cells, and airway hyperresponsiveness. In contrast, a monoclonal antibody against IL-17A (αIL-17A) had no significant effect on airway hyperresponsiveness but did decrease lung neutrophils, macrophages, and IL-17 CD4 T cells. Targeting the IL-23 pathway did not significantly change IL-5 or IL-13 CD4 T cells. Together, these data indicate that airway AcIL-23 mirrored the activity of systemic anti-IL-23 antibody to decrease airway hyperresponsiveness in addition to mixed granulocytic inflammation and that these protective actions were broader than blocking IL-17A or IL-5 alone, which selectively decreased airway neutrophils and eosinophils, respectively. This is the first report of an Anticalin protein engineered to neutralize IL-23 (AcIL-23). Airway administration of AcIL-23 in mice regulated allergen-driven airway inflammation, mucous cell metaplasia, and methacholine-induced airway hyperresponsiveness. In mixed granulocytic allergic lung inflammation, immune regulation of IL-23 was broader than neutralization of either IL-17 or IL-5.
严重哮喘是一种基于临床参数为患者分配的综合征标签，但在严重哮喘病理生物学中存在多种不同的潜在分子表型。哮喘生物标本的免疫表型分析通常包括粒细胞和淋巴细胞的混合物。最近，一部分严重哮喘患者被定义为非 2 型，其特征是与 Th17 CD4 T 细胞和 IL-17 水平增加相关的中性粒细胞富集炎症。在这里，我们使用一种过敏原驱动的增加 IL-17 和混合粒细胞肺部炎症的小鼠模型，来确定专门结合 IL-23 的 Anticalin 蛋白的上游调节对其的影响。气道给予 IL-23 结合 Anticalin 蛋白（AcIL-23）可减少肺部中性粒细胞、嗜酸性粒细胞、巨噬细胞、淋巴细胞、IL-17 CD4 T 细胞、黏液细胞化生和乙酰甲胆碱诱导的气道高反应性。用单克隆抗体（IL-23p19；αIL-23）选择性靶向 IL-23 也可减少巨噬细胞、IL-17 CD4 T 细胞和气道高反应性。相比之下，抗 IL-17A 的单克隆抗体（αIL-17A）对气道高反应性没有显著影响，但确实减少了肺部中性粒细胞、巨噬细胞和 IL-17 CD4 T 细胞。靶向 IL-23 途径不会显著改变 IL-5 或 IL-13 CD4 T 细胞。总的来说，这些数据表明，气道 AcIL-23 反映了全身抗 IL-23 抗体的活性，除了混合粒细胞炎症外，还可降低气道高反应性，并且这些保护作用比单独阻断 IL-17A 或 IL-5 更广泛，后者分别选择性地减少气道中性粒细胞和嗜酸性粒细胞。这是第一个报告的针对 IL-23 （AcIL-23） 的 Anticalin 蛋白工程。在小鼠中气道给予 AcIL-23 可调节过敏原驱动的气道炎症、黏液细胞化生和乙酰甲胆碱诱导的气道高反应性。在混合粒细胞性变应性肺炎症中，IL-23 的免疫调节作用比中和 IL-17 或 IL-5 更广泛。
