Extracellular vesicles (EVs), tiny sacs released from myelin-producing cells called oligodendrocytes, may help dampen the immune system’s attack against myelin, whose loss is the hallmark of multiple sclerosis (MS), a new mouse study shows.
The findings suggest that oligodendrocytes-released EVs could work as an universal immunotherapy for MS patients.
The study “Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice” was published in the journal Science Translational Medicine.
In people with MS, the body’s immune system mistakenly recognizes myelin — the fatty protective coating surrounding the fibers, or axons, of nerve cells (neurons) — as a foreign molecule and attacks it. This causes inflammation and damage to brain nerve cells.
Inducing immune tolerance — a state in which myelin antigens (tiny pieces of proteins, displayed as flags, that can trigger an immune response) no longer are attacked by the immune system — has been a longstanding goal in MS research.
However, the source of the most relevant myelin antigens triggering the immune response remained uncertain.
“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,” Abdolmohamad Rostami, MD, PhD, the study’s lead author, said in a press release. Rostami is professor and chairman of the department of neurology at Sidney Kimmel Medical College – Thomas Jefferson University in Pennsylvania.
Previous studies in animal models have relied on the intravenous (into-the-vein) injection of myelin antigens — either alone or in combination — to induce immune tolerance. However, in humans this showed limited success and concerns arose whether intravenously injected myelin antigens could worsen disease rather than ease it.
“Previous studies have used single myelin antigens or combinations of antigens to prevent auto-immunity in animal models, but in humans they have had limited success,” Rostami said.
In their study, researchers at Thomas Jefferson University developed a therapeutic approach to restore immune tolerance in the central nervous system (CNS, brain and spinal cord) of MS by turning to oligodendrocytes, the cells responsible for myelin production.
Specifically, they used EVs, tiny sacs surrounded by a fat layer, released from oligodendrocytes grown in the lab. The EVs, they found, contained the more relevant myelin antigens, which the researchers hypothesized could halt the immune attack.
“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,” said Rostami. “It covers all the bases.”
To test the hypothesis that oligodendrocytes-EVs potentially could restore immune tolerance, researchers injected EVs into three mouse models of MS — representing chronic disease and relapsing-remitting disease.
The EVs first were given either prophylactically (before disease onset), or as a therapy after the animals developed symptoms.
Results showed that the oligodendrocyte-EVs lessened the disease in both prophylactic and therapeutic regimens in all three mouse models. Given prophylactic, the EVs prevented the onset of symptoms, such as impaired mobility and paralysis; therapeutic EVs lessened disease severity with the animals being able to walk again. These effects were seen for at least two weeks after the last injection, at the time the animals were sacrificed.
Moreover, EVs protected the animals from loss of myelin and damage to nerve cells.
“The antigens involved in the auto-immune response can differ between MS patients, and even change over time in an individual patient,” said Rostami. “The fact that our approach was effective in different experimental models shows this could act as a universal therapy.”
Researchers then performed further experiments to understand how the oligodendrocyte-EVs exerted their therapeutic effects.
EVs are known to work as vehicles of communication between cells, as they carry information from one cell to another. Researchers found that the oligodendrocyte-EVs were preferentially received by cells of the immune system, namely monocytes and neutrophils. They also were able to identify monocytes as the cells that mediated immune tolerance to myelin.
The team reported that injection of monocytes that acquired these oligodendrocyte-EVs led to an immune tolerance state and triggered the death of immune T-cells that mediate the attack against myelin in the MS mouse models.
Importantly, the remaining cells of the immune system (apart from T-cells) were intact, meaning that the EVs did not cause any weakening of the immune system, but rather targeted the MS-causing immune cells.
“This is a huge advantage of our antigen-specific method over current therapies, which are like a sledgehammer to the immune system,” said Rostami.
Researchers believe the findings can be translated to the clinic, as they were able to isolate EVs carrying multiple myelin antigens from human oligodendrocytes.
Overall, “given that Ol [oligodendrocytes]-EVs contain most, or possibly all, relevant myelin Ags [antigens], they have the potential to induce Ag-specific tolerance and suppress disease driven by an immune response against myelin,” the researchers wrote.
Moreover, since oligodendrocyte-EVs contain multiple myelin antigens this means that they’re likely to work as an “off-the-shelf” therapy, without the need to tailor the EVs for each patient, making it a potential “universally applicable Ag [antigen]-specific MS therapy,” the team concluded.
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