MS Progression Stopped by Targeting T Helper Cells with CXCR6 Receptor in Mouse Model - Multiple Sclerosis News Today

Targeting the chemokine receptor CXCR6, a protein at the surface of a certain group of T helper cells, prevented the development of multiple sclerosis (MS) in a mouse model of the disease, a study reports.

Its findings suggest that antibodies targeting T helper cells — known drivers of MS — that carry the CXCR6 receptor may slow or prevent MS progression without broadly dampening the immune system.

The study “SerpinB1 controls encephalitogenic T helper cells in neuroinflammation” was published in the journal PNAS.

Immune CD4 positive T-cells, known as T helper cells, play an important role in the autoimmune reaction against myelin (the protective coat surrounding neurons), the hallmark of MS. These cells are characterized by high levels of two pro-inflammatory molecules, called  IL1β and IL-23, that help to sustain the immune reaction. However, the mechanisms through which these autoreactive cells arise is still unclear.

Researchers at the Boston Children’s Hospital discovered a link between IL-23 and a protein called SerpinB1 (Sb1) that helps autoreactive T-cells escape suicide and expand uncontrollably.

They first observed that in mice with experimental autoimmune encephalomyelitis (EAE), a condition that mimics key pathological features of MS in humans, a subset of CD4 positive T-cells had high levels of Sb1, along with Rorc and IL17a, two inflammatory factors.

Researchers then tested how Sb1 affects the autoreactivity of T-cells. Deleting the Sb1 gene from T helper cells led to a significant decrease in the cell’s ability to infiltrate the spinal cord, lessening EAE symptoms.

A genetic screening of T-cells derived from mice without the Sb1 gene revealed that these cells were lacking the chemokine receptor CXCR6. Right away, the team saw an opportunity to use this marker as a way to target these cells.

By using an antibody against CXCR6, the researchers were able to replicate their previous results, those showing that depleting Sb1-expressing T-cells halted the development of MS.

“We’ve demonstrated in mice you can target these cells and get rid of them,” Eileen Remold-O’Donnell, PhD, of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, and the study’s senior author, said in a press release.

“We don’t know if this approach would be appropriate for all cases of MS, but it could be effective in the early inflammatory stages of the disease, and in targeting newly formed cells during disease exacerbations,” Remold-O’Donnell added.

To test whether CXCR6 would also be relevant for human disease, researchers investigated whether cells from patients with inflammatory autoimmune diseases also carried CXCR-6 positive cells.

They observed that samples of synovial fluid (joint liquid) from patients with inflammatory autoimmune arthritis had high levels of CXCR6-positive T helper cells, whereas peripheral blood samples had not. Similarly, blood samples from MS patients and healthy controls showed no signs of CXCR6-positive cells.

This evidence supports that CXCR6-positive cells specifically expand in active disease sites, and can be targeted to mitigate autoimmune diseases without attacking other immune cells.

“Many drugs have been developed to treat autoimmune diseases, such as glucocorticoids and cytotoxic reagents,” said Lifei Hou, PhD, the study’s first author. “However, none selectively target pathogenic [disease-related] T-cells, and long-term use of immunosuppressive agents results in broad immunosuppression and compromised immune defenses. Therapeutics with better selectivity, safety, and efficacy are needed.”

These findings “suggest that therapies to regulate Sb1 levels or, more realistically, strategies to deplete CXCR6-marked TH [T helper] cells hold promise for mitigating autoimmune disorders such as MS,” the study concluded.

“Importantly, we discovered that cell surface CXCR6 is an exquisite marker of pathogenic T helper cells and demonstrated that anti-CXCR6 treatment has potential to prevent or mitigate MS,” its researchers added.

Remold-O’Donnell and Hou have filed a patent based on their discovery, and formed a company, called Edelweiss Immune, which will be carrying this research forward.

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Sunday, 17 November 2019
 
 

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