Dual Inhibition of Interleukin-23 and Interleukin-17 Offers Superior Efficacy in Mouse Models of Autoimmunity
Dual Inhibition of Interleukin-23 and Interleukin-17 Offers Superior Efficacy in Mouse Models of Autoimmunity
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DOI：
10.1124/jpet.115.224246
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发表时间：
2015-08-01
影响因子：
3.5
通讯作者：
Salter-Cid, Luisa M.
中科院分区：
文献类型：
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作者：
Mangan, Paul R.;Su, Linhui Julie;Salter-Cid, Luisa M.
靶向白细胞介素（IL）-23或IL-17的疗法在治疗辅助性T细胞17（Th 17）驱动的自身免疫性疾病中显示出前景。虽然IL-23是IL-17的关键驱动因子，但对IL-23和IL-17的非冗余和独立功能的认识促使人们认为，相对于单独靶向任一细胞因子，IL-23和IL-17的双重抑制可以为治疗自身免疫性疾病提供甚至更大的功效。为了验证这一假设，我们产生了IL-23和IL-17的选择性抑制剂，并在体外和体内测试了单独治疗与联合治疗的效果。在体外，使用鼠Th 17细胞和NIH/3 T3成纤维细胞的新培养系统，我们发现IL-23和IL-17的抑制完全抑制了Th 17细胞的IL-23依赖性IL-22的产生，并协同阻断NIH/3 T3细胞的IL-17依赖性IL-6分泌，使其水平低于单独的抑制剂。在体内，在咪喹莫特诱导的皮肤炎症模型中，以及在髓鞘少突胶质细胞糖蛋白肽诱导的实验性自身免疫性脑脊髓炎模型中，我们证明了IL-17和IL-23的双重抑制在减少疾病方面比单独靶向任一种细胞因子更有效。总之，这些数据支持IL-23和IL-17两者的中和可以提供针对Th 17介导的自身免疫的增强的益处的假设，并且为旨在双重靶向IL-23和IL-17的治疗策略提供基础。
Therapies targeting either interleukin (IL)-23 or IL-17 have shown promise in treating T helper 17 (Th17)-driven autoimmune diseases. Although IL-23 is a critical driver of IL-17, recognition of nonredundant and independent functions of IL-23 and IL-17 has prompted the notion that dual inhibition of both IL-23 and IL-17 could offer even greater efficacy for treating autoimmune diseases relative to targeting either cytokine alone. To test this hypothesis, we generated selective inhibitors of IL-23 and IL-17 and tested the effect of either treatment alone compared with their combination in vitro and in vivo. In vitro, using a novel culture system of murine Th17 cells and NIH/3T3 fibroblasts, we showed that inhibition of both IL-23 and IL-17 completely suppressed IL-23-dependent IL-22 production from Th17 cells and cooperatively blocked IL-17-dependent IL-6 secretion from the NIH/3T3 cells to levels below either inhibitor alone. In vivo, in the imiquimod induced skin inflammation model, and in the myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis model, we demonstrated that dual inhibition of IL-17 and IL-23 was more efficacious in reducing disease than targeting either cytokine alone. Together, these data support the hypothesis that neutralization of both IL-23 and IL-17 may provide enhanced benefit against Th17 mediated autoimmunity and provide a basis for a therapeutic strategy aimed at dual targeting IL-23 and IL-17.