The novel small-molecule TPN10456 inhibits Th17 cell differentiation and protects against experimental autoimmune encephalomyelitis

Cellular & Molecular Immunology, 2020 · DOI: https://doi.org/10.1038/s41423-020-00566-8 · Published: October 27, 2020

Simple Explanation

Multiple sclerosis (MS) is an autoimmune disease where the body's immune system attacks the central nervous system, leading to inflammation and damage. Th17 cells, a type of immune cell, play a key role in the development of MS. Researchers have discovered a small molecule called TPN10456 that can suppress the differentiation of Th17 cells. This molecule appears to inhibit the development of pathogenic Th17 cells, which are particularly harmful in MS. In experiments with mice that mimic MS, TPN10456 treatment reduced the severity of the disease, lessened immune cell infiltration into the central nervous system, and decreased demyelination. This suggests TPN10456 could be a potential therapeutic agent for treating MS.

Study Duration

Not specified

Participants

Naive CD4+ T cells isolated from the spleens of 6- to 8-week-old C57BL/6 mice and healthy human peripheral blood mononuclear cells

Evidence Level

Level Not specified, Animal Model (EAE mice) and In vitro studies

Key Findings

1
TPN10456 inhibits Th17 cell differentiation in a dose-dependent manner. The addition of TPN10456 resulted in a dose-dependent reduction in the frequency of IL-17A-producing cells.
2
TPN10456 reduces the severity of experimental autoimmune encephalomyelitis (EAE) in mice. TPN10456 can markedly inhibit the disease severity of EAE and reduce disease incidence compared with the vehicle group.
3
TPN10456 treatment leads to a reduction of leukocyte infiltration and inflammatory foci in the spinal cord of EAE mice. We found TPN10456 treatment leads to a dramatic reduction of leukocyte inﬁltration and inﬂammatory foci in the spinal cord than the vehicle group

Research Summary

This study investigates the effects of the small-molecule TPN10456 on Th17 cell differentiation and its potential therapeutic role in multiple sclerosis (MS). The research demonstrates that TPN10456 effectively suppresses Th17 cell differentiation, particularly pathogenic Th17 cells, both in vitro and in vivo. The study uses the experimental autoimmune encephalomyelitis (EAE) mouse model to assess the impact of TPN10456 on MS-like symptoms. The results show that TPN10456 treatment significantly alleviates EAE severity, reducing clinical scores, inflammatory cell infiltration, and demyelination in the central nervous system. RNA-sequencing analysis revealed that TPN10456 downregulates genes related to Th17 cells. The expression of genes related to Th17 cells, including Il17a, Il23r, Tgfb3, Ccr6, and Rora, were reduced

Practical Implications

Potential Therapeutic Agent for MS

TPN10456 may represent a promising therapeutic agent for the treatment of MS due to its ability to suppress Th17 cell differentiation and alleviate EAE symptoms in mice.

Targeted Th17 Inhibition

The selective inhibition of pathogenic Th17 cells by TPN10456 suggests a more targeted approach to treating autoimmune diseases, potentially minimizing broad immunosuppressive effects.

Drug Development

The study provides a basis for further development and investigation of TPN10456 as a novel drug for MS patients.

Study Limitations

1
The study is primarily based on in vitro experiments and animal models, requiring further validation in human clinical trials.
2
The exact mechanisms by which TPN10456 inhibits Th17 cell differentiation need further investigation.
3
The long-term effects and potential side effects of TPN10456 treatment were not assessed in this study.

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