Tysabri May Promote Inflammatory B-Cell Activation in MS Patients, Study Says

Tysabri May Promote Inflammatory B-Cell Activation in MS Patients, Study Says
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Tysabri (natalizumab), an effective T-cell targeting treatment for multiple sclerosis (MS), seems to also promote the activation of pro-inflammatory immune B-cells in people with this disease, a study found.

The study, “Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients,” was published in the Journal of Neuroinflammation.

Natalizumab, sold under the brand name Tysabri by Biogen, is an antibody-based therapy that aims to reduce inflammation in people with relapsing-remitting multiple sclerosis (RRMS) by preventing immune cells from entering the brain.

Medications that work by modulating and toning down the immune system to keep inflammation in check are known as disease-modifying therapies (DMTs). In addition to Tysabri, DMTs used to treat RRMS include dimethyl fumarate (sold as Tecfidera by Biogen), fingolimod (sold as Gilenya by Novartis), and glatiramer acetate (sold as Copaxone by Teva Pharmaceutical).

All these medications usually interfere with T-cells, a type of immune cells programmed to find and eliminate anything the immune system sees as a threat. T-cells are often the main source of tissue inflammation.

However, “relatively little is known on how these MS drugs may influence B-cells, and if so, how this may contribute to their therapeutic efficacy,” the investigators wrote.

B-cells are immune cells responsible for the production of antibodies against substances seen as threats by the immune system. Research has suggested that B-cells are equally important as T-cells in MS development.

Researchers at the University Medical Center, Robert-Koch-Straße in Göttingen, Germany, set out to investigate the effects of four different types of DMTs on B-cells from RRMS patients.

They started by isolating peripheral blood mononuclear cells (PBMCs) from RRMS patients who had been followed at the Clinical MS Center of the University Medical Center Göttingen between 2015 and 2018. PBMCS are immune blood cells, namely lymphocytes, monocytes, and dendritic cells.

Then, using a technique called flow cytometry, the researchers measured the numbers of B-cells in patients’ PBMC samples, and investigated the properties of the B-cells found. These included, for instance, assessing the presence of markers of B-cell maturation, differentiation, and cytokine production. (Cytokines are molecules that mediate and regulate the body’s immune and inflammatory response.)

In total, researchers collected PBMCs from 95 RRMS patients, including 21 treated with Tecfidera, 20 with Tysabri, 18 with Copaxone, 17 with Gilenya, and 19 who were untreated and served as controls.

The team found that, compared to untreated MS patients, the group treated with Gilenya showed a reduced B-cell abundance in the blood, while Tysabri’s use resulted in a significant increase of B-cells. Tecfidera and Copaxone had no detectable effect on the number of B-cells.

Looking at the effects of the four DMTs on B-cell properties, the team found that while Copaxone seemed to have only a minor impact on these cells, Tecfidera and Gilenya strongly inhibited (blocked) the production of pro-inflammatory cytokines triggered by B-cells.

Tysabri, in contrast, seemed to promote B-cell differentiation and activation, as well as the production of pro-inflammatory cytokines. This effect was clear in samples taken from the same patient before and after treatment with the therapy, and also when comparing PBMC samples from patients treated with Tysabri to untreated controls. (Activated cells are cells that change in response to a stimulus.)

“Despite the fact that all investigated agents have proven efficacy in large clinical trials, our data showed that DMF [Tecfidera], FTY [Gilenya], GA [Copaxone], and NAT [Tysabri] exerted differential, in parts even opposing effects on the composition and properties of peripheral B-cells,” the researchers wrote.

“Possible clinical consequences of these complex alterations yet need to be established,” they added.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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