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Virginia Mason Team IDs Signaling Pathway, Proteins that Could Help Prognose MS Patients

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Researchers at the Benaroya Research Institute at Virginia Mason Medical Center have identified protein signaling pathways involved in effector T-cell resistance in multiple sclerosis.

The pathways, which revolve around the cytokine IL-6, could prove a source of biomarkers for predicting disease progression and severity, Jane Buckner, a BRI researcher and leader of the study, told ProteoMonitor.

In effector T-cell resistance, effector T-cells develop the ability to counter suppression by regulatory T-cells. The phenomenon has been observed in a variety of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and psoriasis, but it had not previously been described in MS, Buckner said.

"There have been quite a few studies looking at how well regulatory T-cells work in MS," she said, noting that a number of these studies had found deficiencies in MS patients' regulatory T-cells.

However, she said, there has been little work in MS looking at the question from the opposite perspective – investigating whether there was something different about MS patients' effector T-cells that would prevent their suppression even in the presence of a healthy, functional complement of regulatory T-cells.

"We … isolated that question and asked, 'If [an MS patient] has normal functioning regulatory T-cells, can they suppress the effector T-cells?'" Buckner said. "And in the majority of MS patients, they couldn't."

In the study, which was published this week in Science Translational Medicine, the researchers examined two cohorts of patients – an initial set of 14 followed by a second cohort of 10, finding in both cohorts that the presence of effector T-cell resistance identified patients with more severe forms of the disease.

To investigate the causes of the observed resistance, the BRI team looked to the cells' cytokine exposure – a factor that has been implicated in the phenomenon in other autoimmune diseases.

In particular, they looked at the cytokine IL-6, which has been linked to effector T-cell resistance in psoriasis.

Using a Luminex bead-based assay, they measured levels of ten cytokines in the patients and healthy controls, but found no differences between the two groups save for increased levels of IP-10 in the MS group, a finding that had been observed in a previous study.

Looking at the effector T-cells, themselves, however, the researchers identified significantly heightened levels of phosphoSTAT3 in the MS patients upon stimulation with IL-6. This elevated phosphoSTAT3 was associated with an increase in the expression of the IL-6 receptor IL-6Rα, suggesting, Buckner said, that effector T-cell resistance in MS is linked not to increased levels of IL-6 itself but rather to increased expression of its receptor, which makes the cell – and the STAT3 pathway – more sensitive to its stimulation.

This, she noted, is a different mode of action from that observed in diseases like psoriasis where resistance has been linked to heightened levels of IL-6 itself.

"That has implications therapeutically," Buckner said. "Lowering IL-6 [in such patients] may be useful, but you may actually have to target the [STAT3] signaling pathway in the cell so that once it senses the IL-6 you block the signaling."

The findings could also prove useful from a prognostic and diagnostic perspective, Buckner said, noting that given the observed links to MS, effector T-cell resistance and the related heightened levels of IL-6Rα expression and STAT3 signaling could be markers for disease severity.

Patients exhibiting these features had significant levels of disease flare-ups and MRI changes over the preceding two years, while such events were absent in patients with milder instances of MS.

Larger studies are needed before any firm conclusions can be drawn, Buckner noted, but, she said, if the initial results hold up, such markers could be helpful in guiding therapy in MS patients.

"If you were a patient who was likely to have very inactive disease with not many flares in the next several years, you might want to avoid [drug treatment]," she said. "Whereas if I could tell you with this test that you were a patient who was likely to have more aggressive disease, it could push you earlier toward treating that with some of the therapeutics that are now available."

Buckner and her colleagues are now "very interested" in putting together a longitudinal prospective trial following up on the findings of the Science Translational Medicine paper.

"Now what we need to do is look at patients as they come in and are newly diagnosed with MS and see if this is a phenomenon that will help us predict what happens to them over time," she said.

She added that the findings also suggest that anti-IL6R therapeutics like tocilizumab – sold by Roche under the name Actemra as a therapy for rheumatoid arthritis – could prove useful in MS patients exhibiting effector T-cell resistance linked to heightened IL-6Rα expression.

"We're not currently planning any clinical trials, but I hope the data from this paper could help move people toward thinking about a therapeutic trial [targeting] that pathway," Buckner said.

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