Targeting Oct1 Protein in T-cells Might Prevent Autoimmune Reactions, MS Mouse Study Finds

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Targeting a protein found in immune T-cells called Oct1 may help prevent the misguided immune response seen in autoimmune diseases like multiple sclerosis (MS), a study shows. Most importantly, a lack of Oct1 does not influence the immune system’s ability to fight viral infections.

The study “T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response” was published in the Journal of Neuroinflammation.

MS is caused by an abnormal immune response, with a group of T-cells — called CD4- and CD8-positive T-cells — infiltrating the central nervous system and attacking myelin, the protective coat of nerve fibers.

Ideally, immunosuppressive therapies would shut down this unwanted immune response without affecting the immune system’s ability to fight infections.

Previous studies showed that the Oct1 protein is found in CD4-positive T-cells when they re-encounter an antigen — the molecule that triggers an immune response. But Oct1 is not necessary for the immune system to fight pathogens or to T-cell development.

Based on this knowledge, researchers at the University of Utah School of Medicine hypothesized that the loss of Oct1 could protect against autoimmunity diseases, such as MS, without jeopardizing the capacity of the immune system to fight pathogens or infections.

To test this, they deleted the gene coding for Oct1 specifically in CD4+ T-cells in the experimental autoimmune encephalomyelitis (EAE) mouse model, a well-established model for human MS.

Results showed that mice lacking Oct1 in these T-cells had a lower number of T-cell infiltrates, with theCD4+ T-cells secreting significantly fewer pro-inflammatory cytokines, like interleukin (IL)-17 and interferon-gamma, in the animal’s spinal cords compared to a control and untreated group of mice. Lack of Oct1 also lowered inflammation and eased paralysis.

The degree of demyelination— the damage to the myelin sheath that surrounds and protects nerves — was reduced by half when the Oct1 gene was deleted in T-cells.

“These data indicate that loss of Oct1 in T-cells strongly protects animals from clinical symptoms of EAE, and that this protection is associated with decreased CNS [central nervous system] T-cell proinflammatory cytokine expression,” the researchers wrote.

Next, the scientists tested Oct1 deletion in a virus infection scenario. They observed that all mice lacking Oct1 were able to clear a JHMV mouse hepatitis virus infection, although at a slower pace than control mice.

“Our expectation was that protection from a model of MS would go hand-in-hand with poor defense against viruses, however that was not the case,” Dean Tantin, PhD, a geneticist in the department of pathology at University of Utah Health, and the study’ co-lead author, said in a news release written by Trevor Quirk.

Overall, the results suggest that targeting Oct1 could suppress autoimmune disease without a considerable and negative effect on the immune system’s virus-fighting capacity.

In fact, in vitro (in the lab) experiments showed that a lack of Oct1 made T-cells less reactive, and resulted in increased activity of genes that protect against autoimmunity, like CTLA4.

Tantin believes that transcription factors, proteins like Oct1 that regulate gene expression, could be used to translate these results into a treatment.

“You’re going down to the DNA where the genes are regulated,” Tantin said. “Broadly speaking, going forward I think transcription factors are an opportunity to get at the root of the problem.”

However, researchers emphasized that targeting the Oct1 protein may affect the immune system’s ‘memory’ for retrieving an attack against a pathogen it has seen before.

“If you delete this factor you impair the ability to establish new immune memory; so that is clearly a potential side effect,” he added.

But MS largely affects adults “who have already formed a lot of their immune memory and have been vaccinated,” meaning these people have a well-established immune repertoire, so this side-effect may not pose a big problem, Tantin said.

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