Mangan Paul R, Su Linhui Julie, Jenny Victoria, Tatum Andrea L, Picarillo Caryn, Skala Stacey, Ditto Noah, Lin Zheng, Yang XiaoXia, Cotter Pete Z, Shuster David J, Song Yunling, Borowski Virna, Thomas Rochelle L, Heimrich Elizabeth M, Devaux Brigitte, Das Gupta Ruchira, Carvajal Irvith, McIntyre Kim W, Xie Jenny, Zhao Qihong, Struthers Mary, Salter-Cid Luisa M
Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.)
Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
J Pharmacol Exp Ther. 2015 Aug;354(2):152-65. doi: 10.1124/jpet.115.224246. Epub 2015 May 26.
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.
靶向白细胞介素（IL）-23或IL-17的疗法在治疗由辅助性T细胞17（Th17）驱动的自身免疫性疾病方面已显示出前景。尽管IL-23是IL-17的关键驱动因子，但对IL-23和IL-17非冗余且独立功能的认识促使人们认为，相对于单独靶向任何一种细胞因子，同时抑制IL-23和IL-17可能在治疗自身免疫性疾病方面具有更高的疗效。为了验证这一假设，我们制备了IL-23和IL-17的选择性抑制剂，并在体外和体内测试了单独使用这两种抑制剂以及它们联合使用的效果。在体外，我们使用一种新型的小鼠Th17细胞和NIH/3T3成纤维细胞培养系统，结果表明，抑制IL-23和IL-17可完全抑制Th17细胞中IL-23依赖性IL-22的产生，并协同阻断NIH/3T3细胞中IL-17依赖性IL-6的分泌，使其水平低于单独使用任何一种抑制剂时的水平。在体内，在咪喹莫特诱导的皮肤炎症模型以及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，与单独靶向任何一种细胞因子相比，同时抑制IL-17和IL-23在减轻疾病方面更有效。总之，这些数据支持了以下假设：中和IL-23和IL-17可能为对抗Th17介导的自身免疫提供更大益处，并为旨在同时靶向IL-23和IL-17的治疗策略提供了依据。
