MS Brain Lesions Linked to Early-life Viral Infection in Mice, Way of Blocking Inflammatory Spread Seen

MS Brain Lesions Linked to Early-life Viral Infection in Mice, Way of Blocking Inflammatory Spread Seen

An experimental treatment known as OB-002, that works to block an inflammatory molecule in the brain, prevented the development of lesions there after an early-in-life viral infection in a mouse model of multiple sclerosis (MS).

The research “Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice,” was published in the journal Science Translation Medicine.

The association between viral infections in childhood and the risk of later developing autoimmune disorders such as MS is supported by epidemiological studies — studies of diseases in populations of people or animals. Still, the biological mechanism or process linking the two remains unknown.

A research team from Switzerland and Germany found that viral infection in the brains of mice early in life, but not at a later age, worsened those MS symptoms evident in a brain, like lesions, at sites where the virus had resided but was cleared. These changes were induced by immune T-cells containing the CD4 cell surface marker and specific for myelin, the protective layer of nerve fibers that is destroyed in MS.

Sites of infection showed a chronic inflammatory profile with brain-resident memory T-cells — which protect against recurrent or reactivated infection — containing CCL5 (also known as RANTES). This pro-inflammatory molecule has been suggested to be involved in myelin formation and cellular metabolism.

“Early-life infection of mouse brains imprinted a chronic inflammatory signature that consisted of brain-resident memory T-cells expressing the chemokine (C-C motif) ligand 5 (CCL5),” the researchers wrote.

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Researchers then found that blocking CCL5 signaling using OB-002, Orion Biotechnology Canada’s CCR5 receptor blocker, prevented the formation of brain lesions in the MS mouse model.

Of note, in mouse and human brains, T-cells containing CCL5 are mainly located at sites with activated microglia — innate immune cells in the central nervous system associated with the development of MS lesions and with myelin loss.

Overall, the results showed that “transient brain viral infection early in life worsened lesion development and symptoms in a mouse model of autoimmune disease,” and that “autoimmune lesions were spatially associated with areas of previous viral infection in mice,” the researchers wrote.

“Mechanistically, early-life viral infection induced a persistent population of CCL5–expressing brain-resident memory T-cells that promoted a long-lasting proinflammatory environment. Blockade of CCL5 signaling prevented the increased predisposition to autoimmunity in the mouse model,” the team added.

“It is very exciting to have identified a possible pathway linking virus infection early in life to MS pathology, and intriguing that it should be dependent on the activation of a single chemokine receptor,” Doron Merkler, the study’s senior author and a professor at University of Geneva and University Hospitals of Geneva, said in a press release.

Oliver Hartley, a study co-author and Orion’s vice-president for drug discovery, added: “We are thrilled to see that OB-002 shows such high efficacy in this preclinical context. These data provide a clear rationale to move forward with the development of OB-002 as [a] novel agent for the treatment of MS.”

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has studied Biochemistry also at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario, in London, Ontario. His work ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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