| First Author | Aqel SI | Year | 2019 |
| Journal | Clin Exp Immunol | Volume | 196 |
| Issue | 2 | Pages | 215-225 |
| PubMed ID | 30615197 | Mgi Jnum | J:295117 |
| Mgi Id | MGI:6459659 | Doi | 10.1111/cei.13258 |
| Citation | Aqel SI, et al. (2019) Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development. Clin Exp Immunol 196(2):215-225 |
| abstractText | 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. |
