Targeting Inflammatory Th17 Cells to Slow MS Disability Possible with Fewer Side Effects, Study Suggests

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Th17 cell research

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Scientists may have found a way to manipulate T-helper 17 (Th17) cells so as to lower their ability to trigger inflammation, delaying the onset ofĀ multiple sclerosisĀ (MS) in a mouse model and slowing its progression without affecting the entire immune system.

Their findings may lead to new treatments with fewer side effects forĀ MS and other Th17-driven autoimmune diseases.

The study, ā€œThe nuclear receptor REV-ERBĪ± modulates Th17 cell-mediated autoimmune disease,ā€ was published in the journal Proceedings of the National Academy of Sciences.

Th17 cells are a subtype of pro-inflammatory T-cells that produce interleukin-17 (IL-17), a molecule that, when produced in excess because Th17 cells are overactive, is associated with the development of such autoimmune diseases as MS, rheumatoid arthritis, andĀ psoriasis.

In MS, dysregulated (overactive) Th17 cells play a key role in the destruction of the myelin, the protective layer of nerve cells, that is a hallmark of the disease.

A molecule that regulates the production of IL-17 in Th17 cells, called retinoic acid receptor-related-orphan-receptor-gamma t (RORĪ³t), has caught scientists’ attention before as a potential target for treating autoimmune diseases.

However, RORĪ³t is also involved in critical processes for other T-cells in the immune system. Treatment approaches that act to block its activity have, so far, resulted in changes to T-cell numbers and diversity that damage the system’s ability to defend the body against invading virus and other threats.

Researchers at the Salk Institute found a potential way to suppress RORĪ³t activity, limiting IL-17 production, without harming the rest of the immune system.

Their work showed that REV-ERBĪ±, a molecule known to suppress the activity of RORĪ³t by competing in a variety of processes for the same binding site on the DNA of cells, also competed for that site with Th17 cells.

When the team specifically increased the levels of REV-ERBĪ± in Th17 cells grown in the lab, both RORĪ³t activity and Il-17 production were suppressed. Adding SR9009, a synthetic molecule that boosts the activity of REV-ERBĪ±, to Th17 cells led to similar outcomes.

ā€œROR is a gas pedal that drives these helper T cells, but REV-ERB is like the brakes,ā€ Ye Zheng, the studyā€™s co-senior author and an associate professor at Salkā€™s NOMIS Center for Immunobiology and Microbial Pathogenesis, said in a press release.

Researchers then evaluated how these two approaches affected MS development in the experimental autoimmune encephalomyelitis (EAE) mouse model of the disease.

Both increasing the levels of REV-ERBĪ± in T-cells of these mice, and treating the animals with SR9009, significantly delayed disease onset and slowed the progression of symptoms.

“REV-ERBĪ± is induced during Th17 cell differentiation and directly competes with RORĪ³t by binding to [specific] sites to repress the expression of key Th17 cell signature genes,” the scientists wrote.

In contrast to earlier attempts to suppress RORĪ³t, use of SR9009 did not induce changes in T-cell development across the immune system.

Researchers believe their work suggests that boosting REV-ERBĪ± activity through SR9009 lowers inflammation, and without harming the immune system in ways that current RORĪ³t suppressive efforts do.

ā€œThis research opens the door to treating [autoimmune disease] patients without triggering harmful side effects,ā€ said Ronald Evans, co-senior study author and director of Salkā€™s Gene Expression Laboratory.

ā€œA strategy of targeting REV-ERB alone or in combination with RORĪ³ may provide a unique advantage in developing treatments for Th17 cell-mediated autoimmune diseases,ā€ the researchers wrote.

They plan to study the role of REV-ERB in models of other Th17 cell-mediated autoimmune diseases, such as rheumatoid arthritis and psoriasis.