Discovery Projects Unit, HitGen Inc, Building 6, No. 8 Huigu First East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu, 610200, Sichuan, China.
BMC Immunol. 2021 Jan 28;22(1):11. doi: 10.1186/s12865-021-00401-3.
Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. However, a usable psoriatic animal model has been always required for preclinical evaluation of IL17A antagonists. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it's not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition.
On female C57BL/6 mice, with optimization on the usage of IMQ, positive control reagent and anti-mIL17A antibody, a 7-day model with proper testing window, acceptable disease severity as well as high repeatability was developed, and the efficacy of IL17A antagonist can be objectively evaluated by several qualitative and quantitative indices. Meanwhile, we validated the detailed involvement of IL17A signaling in disease progression, confirmed that the expression levels of IL17A and its related cytokines were induced by IMQ application, and its downstream cytokines can be inhibited by IL17A antagonist treatment. In further study, we revealed that IL17A was transient induced by IMQ and directly caused downstream signaling activation. This finding on the kinetical change of IL17A signaling will manifest the pharmacokinetics-pharmacodynamics investigation of IL17A antagonists.
Our work presents the application of a convenient psoriatic animal model in the research and development of IL17A antagonists, meanwhile providing extra evidence for understanding IL17A's role in the progression of IMQ-induced psoriasis model, which manifest the research and development of IL17A antagonists.
白细胞介素-17A（IL-17A）是一种促炎细胞因子，在自身免疫性疾病中起着至关重要的作用，IL-17A 的单克隆抗体已被批准用于银屑病的临床治疗。然而，在进行 IL-17A 拮抗剂的临床前评估之前，一直需要使用可用的银屑病动物模型。咪喹莫特（IMQ）诱导的银屑病模型广泛应用于基础研究，但在常规建模条件下，无法准确显示 IL-17A 拮抗剂的抗银屑病作用。
在雌性 C57BL/6 小鼠中，通过优化 IMQ 的使用、阳性对照试剂和抗 mIL-17A 抗体，开发了一种具有适当测试窗口、可接受的疾病严重程度和高重复性的 7 天模型，可以通过几个定性和定量指标客观评估 IL-17A 拮抗剂的疗效。同时，我们验证了 IL-17A 信号通路在疾病进展中的详细参与，证实了 IMQ 应用诱导了 IL-17A 及其相关细胞因子的表达水平，IL-17A 拮抗剂的治疗可以抑制其下游细胞因子。在进一步的研究中，我们发现 IL-17A 是由 IMQ 瞬时诱导的，并直接导致下游信号通路的激活。这一发现揭示了 IL-17A 信号通路的动力学变化，将体现 IL-17A 拮抗剂的药代动力学-药效学研究。
我们的工作展示了一种方便的银屑病动物模型在 IL-17A 拮抗剂的研究和开发中的应用，同时为理解 IL-17A 在 IMQ 诱导的银屑病模型进展中的作用提供了更多证据，这体现了 IL-17A 拮抗剂的研究和开发。
