Robert Remy, Ang Caroline, Sun Guizhi, Juglair Laurent, Lim Ee X, Mason Linda J, Payne Natalie L, Bernard Claude Ca, Mackay Charles R
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
Australian Regenerative Medicine Institute, Monash University, Victoria, Australia.
JCI Insight. 2017 Aug 3;2(15). doi: 10.1172/jci.insight.94821.
The chemokine receptor CCR6 marks subsets of T cells and innate lymphoid cells that produce IL-17 and IL-22, and as such may play a role in the recruitment of these cells to certain inflammatory sites. However, the precise role of CCR6 has been controversial, in part because no effective monoclonal antibody (mAb) inhibitors against this receptor exist for use in mouse models of inflammation. We circumvented this problem using transgenic mice expressing human CCR6 (hCCR6) under control of its native promoter (hCCR6-Tg/mCCR6-/-). We also developed a fully humanized mAb against hCCR6 with antagonistic activity. The expression pattern of hCCR6 in hCCR6-Tg/mCCR6-/- mice was consistent with the pattern observed in humans. In mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis, treatment with anti-hCCR6 mAb was remarkably effective in both preventive and therapeutic regimens. For instance, in the imiquimod model of psoriasis, anti-CCR6 completely abolished all signs of inflammation. Moreover, anti-hCCR6 attenuated clinical symptoms of myelin oligodendrocyte glycoprotein-induced (MOG-induced) EAE and reduced infiltration of inflammatory cells in the central nervous system. CCR6 plays a critical role in Th17 type inflammatory reactions, and CCR6 inhibition may offer an alternative approach for the treatment of these lesions.
趋化因子受体CCR6可标记产生白细胞介素-17和白细胞介素-22的T细胞亚群和天然淋巴细胞，因此可能在将这些细胞招募到某些炎症部位中发挥作用。然而，CCR6的确切作用一直存在争议，部分原因是在炎症小鼠模型中不存在针对该受体的有效单克隆抗体（mAb）抑制剂。我们利用在其天然启动子（hCCR6-Tg/mCCR6-/-）控制下表达人CCR6（hCCR6）的转基因小鼠规避了这一问题。我们还开发了一种具有拮抗活性的针对hCCR6的完全人源化单克隆抗体。hCCR6在hCCR6-Tg/mCCR6-/-小鼠中的表达模式与在人类中观察到的模式一致。在实验性自身免疫性脑脊髓炎（EAE）和银屑病的小鼠模型中，用抗hCCR6单克隆抗体治疗在预防和治疗方案中均非常有效。例如，在银屑病的咪喹莫特模型中，抗CCR6完全消除了所有炎症迹象。此外，抗hCCR6减轻了髓鞘少突胶质细胞糖蛋白诱导的（MOG诱导的）EAE的临床症状，并减少了中枢神经系统中炎性细胞的浸润。CCR6在Th17型炎症反应中起关键作用，抑制CCR6可能为治疗这些疾病提供一种替代方法。
