Novel small molecule IL‐6 inhibitor suppresses autoreactive Th17 development and promotes Treg development

• Published in: Clinical and experimental immunology 2019-05, Vol.196 (2), p.215-225
• Main Authors: Aqel, S. I., Kraus, E. E., Jena, N., Kumari, V., Granitto, M. C., Mao, L., Farinas, M. F., Zhao, E. Y., Perottino, G., Pei, W., Lovett‐Racke, A. E., Racke, M. K., Fuchs, J. R., Li, C., Yang, Y.
• Format: Article
• Language: English
• Subjects: Adoptive transfer; CD3 antigen; CD4 antigen; Effector cells; Experimental allergic encephalomyelitis; Helper cells; IL‐6; Immunoregulation; Inhibitors; Lymphocytes; Lymphocytes T; Medical innovations; Memory cells; Multiple sclerosis; Myelin; Neurological complications; Original; Signal transduction; small molecule inhibitors; T cell encephalitogenicity; Th17; Transcription; Young adults
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13258

Summary Multiple sclerosis (MS) is the leading cause of non‐traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin‐specific interleukin (IL)‐17‐producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg) CD4 T cells are beneficial for suppressing disease. The IL‐6/signal transducer and activator of transcription 3 (STAT‐3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL‐6 inhibitors, madindoline‐5 (MDL‐5), MDL‐16 and MDL‐101, significantly suppress IL‐17 production in myelin‐specific CD4 T cells in a dose‐dependent manner in vitro. MDL‐101 showed superior potency in suppressing IL‐17 production compared to MDL‐5 and MDL‐16. Treatment of myelin‐specific CD4 T cells with MDL‐101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL‐101 significantly suppressed proliferation and IL‐17 production of anti‐CD3‐activated effector/memory CD45RO+CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL‐6 inhibitors have the potential to shift the Teff : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS. Myelin‐specific IL‐17 producing Th17 cells are a major subset of CD4 T effector cells (Teff) that mediates disease progression in multiple sclerosis (MS) while T regulatory (Treg) CD4 T cells are beneficial for suppressing disease. The IL‐6/STAT‐3 signaling pathway promoted Th17 development and suppressed Treg development. Here we show that a novel small molecule IL‐6 inhibitor madindoline‐101 (MDL‐101) significantly suppressed the proliferation and IL‐17 production of anti‐CD3‐activated effector/memory CD45RO+CD4+ human T cells and promoted human Treg development, demonstrating that MDL‐101 has the potential to shift the Teff : Treg balance, which may provide a novel therapeutic strategy for MS.