Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development
S I Aqel1, E E Kraus1, N Jena1,2
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Clinical and Experimental Immunology
|January 8, 2019
Summary
Novel small molecule inhibitors targeting IL-6 signaling effectively suppress harmful Th17 cells and promote beneficial T-reg cells, offering a potential new treatment strategy for multiple sclerosis (MS).
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Multiple sclerosis (MS) is a leading cause of neurological disability in young adults, with current treatments offering only partial efficacy.
- T helper type 17 (Th17) cells, producing interleukin-17 (IL-17), drive MS pathogenesis, while regulatory T cells (Treg) suppress it.
- The IL-6/STAT-3 pathway critically regulates the balance between pro-inflammatory Th17 and suppressive Treg cells.
Purpose of the Study:
- To investigate novel small molecule inhibitors of IL-6 signaling for their potential therapeutic effects in MS.
- To evaluate the impact of these inhibitors on myelin-specific T cells and their role in experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- In vitro assessment of three novel IL-6 inhibitors (madindoline-5, MDL-16, MDL-101) on IL-17 production in myelin-specific CD4 T cells.
- Evaluation of the encephalitogenic potential of T cells treated with MDL-101 after adoptive transfer.
- Assessment of MDL-101's effects on human CD4 T cell proliferation, IL-17 production, and Treg development.
Main Results:
- All three inhibitors dose-dependently suppressed IL-17 production in myelin-specific CD4 T cells.
- MDL-101 demonstrated superior potency and reduced the encephalitogenic potential of T cells in vitro.
- MDL-101 suppressed IL-17 production and proliferation while promoting Treg development in human CD4 T cells.
Conclusions:
- Novel small molecule IL-6 inhibitors, particularly MDL-101, show promise in modulating the T cell response relevant to MS.
- These inhibitors have the potential to shift the effector T cell (Teff) to regulatory T cell (Treg) balance.
- This approach represents a potential novel therapeutic strategy for ameliorating disease progression in multiple sclerosis.
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