Anti-CD20 therapy reshapes immune cell profiles in MS: Study
Treatment leads to decrease in certain T-cells that target myelin
Anti-CD20 therapies, a type of treatment approved for multiple sclerosis (MS), alter the activity of several types of immune cells, including increasing the levels of certain anti-inflammatory immune cells.
That’s according to the study “Transcriptomic profiling after B cell depletion reveals central and peripheral immune cell changes in multiple sclerosis,” which was published in The Journal of Clinical Investigation.
MS is an inflammatory disorder in which the immune system attacks healthy cells in the brain and spinal cord. In MS, immune cells specifically cause damage to the myelin sheath, which is a fatty coating that helps nerve fibers send electrical signals. Myelin damage leads to dysfunction of nerve cells, ultimately driving the symptoms of MS.
Anti-CD20 therapies for MS include Briumvi, Kesimpta, Ocrevus
Anti-CD20 therapies are a type of MS treatment. Examples include Briumvi (ublituximab-xiiy), Kesimpta (ofatumumab), and Ocrevus (ocrelizumab). These medications work by depleting B-cells, a type of immune cell with a key role in driving MS. By reducing B-cell levels, anti-CD20 therapies can dampen the inflammation that drives MS, ultimately helping to slow disease progression.
Although it’s well-established that anti-CD20 therapies act mainly by killing B-cells, there hasn’t been much study on how these therapies may impact other cells in the immune system. To learn more, a group of scientists at Yale School of Medicine profiled immune cells from people with relapsing-remitting MS before they started on an anti-CD20 therapy, and six months after.
Immune cells were collected from the blood of 18 patients and the cerebrospinal fluid (CSF, the liquid that surrounds the brain and spinal cord) from five patients. Nearly all were treated with Ocrevus, but one patient who provided CSF samples received rituximab, an anti-CD20 therapy sometimes used off-label for MS. Immune cells from people without MS were also analyzed for comparison.
The researchers performed single-cell transcriptomic analyses — in other words, the scientists went cell-by-cell to look at which genes are turned on or off — to draw conclusions about the cells’ inflammatory activity.
“This study provides what we believe to be the first transcriptomic profiling dataset of MS patient blood and CSF pre- and post-B cell depletion therapy,” the researchers wrote.
Results showed anti-CD20 treatment altered the activity of T-cells, a type of immune cell that normally acts like the marshals of the immune system, helping direct other immune cells to attack specific targets.
Normally, T-cells help the immune system attack infectious viruses and bacteria, but in MS, they help direct the attack against myelin. The researchers found that, following anti-CD20 treatment, there was a decrease in certain T-cell populations that showed signs of directing an attack against myelin.
At the same time, there was an uptick in levels of regulatory T-cells (Tregs), which are a specialized type of T-cell that dampen the activity of other immune cells. This normally helps prevent unneeded immune attacks, and in the context of MS, increased Treg counts are expected to help reduce disease-driving inflammation.
“After B cell depletion, we observed shifts in T cell populations … Notably, we found that B cell depletion increased [Treg] frequency and decreased [myelin-attacking] T cell frequency in the blood compartment,” the researchers wrote.
More macrophages show signs of anti-inflammatory activity in CSF
Other types of immune cells were also altered by anti-CD20 treatment, including macrophages, which are immune cells that help remove molecular debris and coordinate inflammatory attacks. Following anti-CD20 treatment, there were more macrophages showing signs of anti-inflammatory activity in the CSF.
“B cell depletion increased the frequencies of CSF macrophages and … these increased cell populations appeared to exhibit an antiinflammatory phenotype,” the researchers wrote.
They also noted that, following anti-CD20 treatment, some immune cells were producing higher levels of a signaling molecule called TNF-alpha. This was somewhat unexpected because TNF-alpha normally helps to drive inflammation. In fact, drugs blocking this signaling molecule are used to treat other inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease.
“This unpredicted increase in TNF-[alpha] shows that [Ocrevus] works in a paradoxical way,” David Hafler, MD, a co-author of the study at Yale School of Medicine, said in a university news story. This finding shows “biology has a richness to it. When these molecules are made, where they’re made, and what cell they’re working on have very different effects.”
Overall, these findings suggest Ocrevus and other anti-CD20 therapies may work not only by depleting B-cells, but also by modulating the immune system in other ways. The researchers stressed, however, that the study was limited to a small number of patients, so more work will be needed to validate the findings.
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