Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach-an-der-Riss, Germany.
Boehringer Ingelheim Ltd, Burlington, Canada.
Respir Res. 2021 May 22;22(1):158. doi: 10.1186/s12931-021-01743-7.
RORγt is a transcription factor that enables elaboration of Th17-associated cytokines (including IL-17 and IL-22) and is proposed as a pharmacological target for severe asthma.
IL-17 immunohistochemistry was performed in severe asthma bronchial biopsies (specificity confirmed with in situ hybridization). Primary human small airway epithelial cells in air liquid interface and primary bronchial smooth muscle cells were stimulated with recombinant human IL-17 and/or IL-22 and pro-inflammatory cytokines measured. Balb/c mice were challenged intratracheally with IL-17 and/or IL-22 and airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Balb/c mice were sensitized intraperitoneally and challenged intratracheally with house dust mite extract and the effect of either a RORγt inhibitor (BIX119) or an anti-IL-11 antibody assessed on airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured.
We confirmed in severe asthma bronchial biopsies both the presence of IL-17-positive lymphocytes and that an IL-17 transcriptome profile in a severe asthma patient sub-population. Both IL-17 and IL-22 stimulated the release of pro-inflammatory cytokine and chemokine release from primary human lung cells and in mice. Furthermore, IL-22 in combination with IL-17, but neither alone, elicits airway hyperresponsiveness (AHR) in naïve mice. A RORγt inhibitor specifically blocked both IL-17 and IL-22, AHR and neutrophilia in a mouse house dust mite model unlike other registered or advanced pipeline modes of action. Full efficacy versus these parameters was associated with 90% inhibition of IL-17 and 50% inhibition of IL-22. In contrast, anti-IL-17 also blocked IL-17, but not IL-22, AHR or neutrophilia. Moreover, the deregulated genes in the lungs from these mice correlated well with deregulated genes from severe asthma biopsies suggesting that this model recapitulates significant severe asthma-relevant biology. Furthermore, these genes were reversed upon RORγt inhibition in the HDM model. Cell deconvolution suggested that the responsible cells were corticosteroid insensitive γδ-T-cells.
These data strongly suggest that both IL-17 and IL-22 are required for Th2-low endotype associated biology and that a RORγt inhibitor may provide improved clinical benefit in a severe asthma sub-population of patients by blocking both IL-17 and IL-22 biology compared with blocking IL-17 alone.
RORγt 是一种转录因子，可促进 Th17 相关细胞因子（包括 IL-17 和 IL-22）的表达，被提议作为严重哮喘的药物靶点。
对严重哮喘支气管活检进行 IL-17 免疫组化染色（通过原位杂交确认特异性）。在气液界面培养原代人小气道上皮细胞和原代支气管平滑肌细胞，用重组人 IL-17 和/或 IL-22 刺激，并测量促炎细胞因子。用 IL-17 和/或 IL-22 对 Balb/c 小鼠进行气管内滴注，测量气道高反应性、促炎细胞因子和气道中性粒细胞浸润。用屋尘螨提取物对 Balb/c 小鼠进行腹腔内致敏和气管内滴注，评估 RORγt 抑制剂（BIX119）或抗 IL-11 抗体对气道高反应性、促炎细胞因子和气道中性粒细胞浸润的影响。
我们在严重哮喘支气管活检中证实了 IL-17 阳性淋巴细胞的存在，并且在严重哮喘患者亚群中存在 IL-17 转录组谱。IL-17 和 IL-22 均可刺激原代人肺细胞释放促炎细胞因子和趋化因子，并在小鼠中引起气道高反应性。此外，IL-22 与 IL-17 联合使用，但单独使用均不能引起无敏小鼠的气道高反应性。一种 RORγt 抑制剂可特异性阻断 IL-17 和 IL-22、AHR 和中性粒细胞浸润，与其他已注册或高级作用机制的药物不同。在一种小鼠屋尘螨模型中，与这些参数的完全疗效相关的是 IL-17 抑制率达到 90%，IL-22 抑制率达到 50%。相比之下，抗 IL-17 也可阻断 IL-17，但不能阻断 IL-22、AHR 或中性粒细胞浸润。此外，这些小鼠肺部的失调基因与严重哮喘活检中的失调基因很好地相关，表明该模型再现了重要的严重哮喘相关生物学。此外，在 HDM 模型中，这些基因在 RORγt 抑制后得到逆转。细胞去卷积表明，负责的细胞是糖皮质激素不敏感的 γδ-T 细胞。
这些数据强烈表明，IL-17 和 IL-22 均是 Th2-低表型相关生物学所必需的，与单独阻断 IL-17 相比，RORγt 抑制剂通过阻断 IL-17 和 IL-22 生物学，可能为严重哮喘患者亚群提供更好的临床获益。
