Blocking Monocytes from Nervous System Eases MS Severity, Early Study Finds

Blocking Monocytes from Nervous System Eases MS Severity, Early Study Finds
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Targeting the MOSPD2 protein may prevent immune cells known as monocytes from entering the central nervous system (CNS), which may significantly ease brain inflammation and myelin damage in multiple sclerosis (MS), a study in mice suggests.

VBL Therapeutics, the company leading the study, has developed several antibodies that target the MOSPD2 protein, and is planning to advance its lead candidate, VB-601, into clinical trials next year.

The research, “MOSPD2 is a Therapeutic Target for the Treatment of CNS Inflammation,” was published in the British Society of Immunology‘s official journal Clinical and Experimental Immunology.

The immune system plays a critical role in MS onset and progression. In patients, immune cells travel from the blood into the brain, where they wrongly attack the protective myelin sheath that covers neurons and initiate a set of inflammatory reactions that eventually cause nerve cells to die.

Immune B-cells and T-cells are seen as the major drivers of this inflammation, but recent studies support monocytes as also instrumental for disease progression.

Monocytes are immune cells that travel in the blood before migrating into tissues, where they can fight threats by engulfing them. But in MS, these cells participate in the process of inflammation by engulfing, or “eating,” pieces of the CNS.

No treatments that lower monocyte infiltration into the CNS are available for MS patients.

MOSPD2 is a protein predominantly found on the surface of monocytes that appears to be essential for their migration. This has led researchers at VBL to investigate whether this protein could be a promising target for blocking monocytes from entering the CNS and preventing MS progression.

The team started by using mice modified to lack the MOSPD2 protein across all cells. These mice developed typically and had a normal immune system, with the amount of B-cells, T-cells, and monocytes across their lymphatic organs being comparable to control mice with a functional MOSPD2.

But animals without this protein showed a significantly lower amount of monocytes in circulation, including a subset of monocytes thought to be the most harmful in MS. Researchers found that such lower levels of monocytes was mainly due to the fact that these cells were unable to exit the bone marrow.

T-cell activation and proliferation, however, was not affected in these animals, indicating that MOSPD2 is not needed for the presentation of antigens — molecules that trigger immune responses — to these cells. Other cells of the monocyte family also continued to function normally in response to pathogens. Levels of inflammatory molecules were also not significantly affected.

Researchers then studied what happened when mice with experimental autoimmune encephalomyelitis (EAE), an established animal model of MS, also lacked the MOSPD2 protein. These animals were seen to be essentially protected from EAE development, exhibiting much lower levels of T-cells and monocytes in their CNS, as well fewer brain regions lacking the protective myelin sheath.

Additional experiments showed that these benefits were due to the lack of MOSPD2 protein in monocytes, regardless of its presence in non-immune cells.

“The data emphasize how important monocytes are in regulating the chronicity of inflammation in this MS model,” Itzhak Mendel, PhD, the paper’s senior author and immunology director of VBL Therapeutics, said in a press release.

While MOSPD2 is only found in monocytes, T-cells in animals lacking MOSPD2 produced fewer pro-inflammatory molecules and more anti-inflammatory proteins in response to stimuli. This suggests that the lack of this protein in monocytes was also dampening T-cell responses.

These findings were essentially replicated when researchers used antibodies against the MOSPD2 protein, rather than depleting the protein. These antibodies significantly inhibited disease development when given before EAE induction, and significantly lessened disease severity when administered at advanced disease stages.

“Our antibodies reduced disease severity not only as a preventive treatment, but also when administered as treatment for established disease,” Mendel said. “This opens us opportunities for potential treatment of relapsing as well as progressive MS disease, in which there is a major unmet need.”

Findings suggest “that MOSPD2 is key in regulating migration of inflammatory monocytes, and that anti‐MOSPD2 [antibodies] constitute a potential therapy for the treatment of CNS inflammatory diseases,” the researchers concluded.

Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
Total Posts: 1,053
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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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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