Researchers headed by a team at Thomas Jefferson University have harnessed myelin antigen-containing extracellular vesicles (EVs) that are released by oligodendrocytes, to create a tolerance therapy for the autoimmune disease multiple sclerosis (MS). The new approach effectively prevents the body’s immune cells from attacking the protective myelin sheath that surrounds nerve cells, which halts MS disease progression, but leaves the rest of the immune system intact. Tests in mouse models showed that the treatment approach counteracted hallmarks of MS such as inflammation and autoimmunity in the nervous system.

“The neat thing about these EVs is that they give us an opportunity to treat the disease in an antigen-specific way, without having to know the exact identity of the target antigen,” explained Abdolmohamad Rostami, MD, PhD, Professor and Chairman of the Department of Neurology at Sidney Kimmel Medical College-Thomas Jefferson University and Vickie and Jack Farber Institute for Neuroscience -Jefferson Health…”It covers all the bases.” Rostami is senior author of the team’s published paper in Science Translational Medicine, which is titled, “Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice.”

MS develops as the body’s immune system attacks the myelin sheath that wraps around central nervous system nerve cells. Current MS therapies aim to counter the inflammatory response by suppressing the immune system, but this can lead to serious side effects, such as a higher risk of infection, or even cancer. What scientists don’t know is which myelin antigens might trigger the immune system attack, and to what extent different antigens may be responsible in different patients, or whether the immune-targeted antigens change with time in the same patient.

“There are many possible immune-activating antigens in the myelin sheath, but the biggest hurdle is that we don’t know which component of myelin is triggering the immune response in MS patients,” explained Rostami. And as the authors further noted, “It is widely believed that MS pathogenesis is driven by autoimmunity against oligodendrocyte (Ol)–produced myelin Ags. However, the relevant self-Ag(s) in MS remains speculative, with the possibility that these Ags differ among patients, and overtime in the same patient.” Previous studies have used single myelin antigens or combinations of antigens to prevent auto-immunity in animal models, Rostami noted, “but in humans they have had limited success.”

To develop their new approach, the researchers turned to the tiny extracellular vesicles that are released by oligodendrocytes that produce the myelin sheath. These EVs can be harvested from cultured oligodendrocytes, and the researchers found that they contain almost all of the relevant myelin antigens. The investigators then used these EVs as the basis for their new therapeutic approach. “ … we developed a therapeutic strategy that relies on oligodendrocyte (Ol)–derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags.” The idea being, that with all of the antigens present, there’d be a higher chance that the EVs could halt the autoimmune attack on myelin.

[The purified oligodendrocyte extracellular vesicles under an electron microscope. [G. Casella et al., Science Translational Medicine (2020)]

Through a series of in vivo experiments the team safely injected the EVs intravenously (i.v.) in three different mouse models of MS, representing early and late stages of the disease. They found that when administered before disease developed, the EVs had a prophylactic effect, preventing the onset of symptoms such as decreased mobility and paralysis. When given after disease onset, the injected EVs significantly reduced severity of disease in all three models, to the point that the animals could walk again. “The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive CD4+ T cells,” the researchers wrote.

“The antigens involved in the autoimmune response can differ between MS patients, and even change over time in an individual patient,” explained Rostami. “The fact that our approach was effective in different experimental models shows this could act as a universal therapy.” The authors further noted, “ … given that Ol-EVs contain most, or possibly all, relevant myelin Ags, they have the potential to induce Ag-specific tolerance and suppress disease driven by an immune response against myelin Ags. Hence, the use of Ol-EVs would sidestep the need to identify relevant myelin Ag(s) in each patient, raising the possibility that Ol-EV/i.v. may be a universally applicable Ag-specific MS therapy.”

Importantly, the researchers found that the experimental therapy only affected immune cells that were attacking the myelin layer. The rest of the immune system remained intact and not weakened at all. “This is a huge advantage of our antigen-specific method over current therapies, which are like a sledgehammer to the immune system,” said Rostami, “and what makes it so novel.”

Translating the approach to the clinical setting, the team found that they were also able to isolate EVs from human-derived oligodendrocytes. These human vesicles, like those from mice, also contained multiple myelin antigens, and therefore could feasibly have the same therapeutic effect in patients. “… we showed that human Ols also released EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy,” the scientists concluded. “These findings introduce an approach for suppressing central nervous system (CNS) autoimmunity in a myelin Ag–specific manner, without the need to identify the target Ag.” The team is now working on getting the intravenous EVs approach patented, which could be a revolutionary step for MS treatment.

Rostami further acknowledged the work of colleagues involved in the research. “This study was made possible by a talented group of scientists, especially Giacomo Casella, a postdoctoral fellow in our laboratory, and Bogoljub Ciric, and Guang-Xin Zhang, faculty members here at Jefferson,” he said.

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