Using Oligodendrocyte Extracellular Vesicles to Induce Tolerance to Myelin as a Treatment for Multiple Sclerosis

In multiple sclerosis, the immune system becomes intolerant towards myelin, the sheathing around nerves that is essential to nervous system function. One class of approach to treating autoimmune diseases of this nature is to produce immune tolerance by delivering more of the problem molecule into the body. The challenge in multiple sclerosis is that it is unclear as to which of the many possible protein sequences is the problem in any given patient, and indeed to build a comprehensive list of such sequences in the first place. Researchers here report on the discovery that the oligodendrocyte cells responsible for building and maintaining myelin sheathing secrete a wide variety of myelin antigens in extracellular vesicles. These vesicles are comparatively easy to harvest from cell cultures, and thus are a good potential basis for an immune tolerance therapy that could work for all multiple sclerosis patients.

Multiple sclerosis (MS) is an autoimmune disorder that develops as the body's immune system attacks the central nervous system. Specifically, it attacks the protective layer surrounding nerve cells, called the myelin sheath. Current MS therapies aim to counter this inflammatory response by suppressing the immune system, which can lead to serious side effects like a higher risk of infection, and even cancer. Researchers have found a way to prevent immune cells from attacking myelin and halt disease progression, while leaving the rest of the immune system intact, in mouse models of MS.

"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. 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." For answers, the researchers turned to cells called oligodendrocytes. These cells wrap their cell membrane around nerve cells to produce the myelin sheath. Tiny sacs called extracellular vesicles (EVs) can be harvested from cultured oligodendrocytes. The researchers found that these EVs contain almost all the relevant myelin antigens. With all of the antigens present, there'd be a higher chance that these vesicles could halt the autoimmune attack on myelin. "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. It covers all the bases."

The researchers were able to safely inject the EVs intravenously in three different mouse models of MS representing early and late stages of the disease. When administered before disease developed, the EVs had a prophylactic effect, preventing the onset of symptoms like decrease in mobility and paralysis. When given after disease onset, EVs significantly reduced severity of disease in all three models, to the point that the animals could walk again. "The antigens involved in the auto-immune response can differ between MS patients, and even change over time in an individual patient. The fact that our approach was effective in different experimental models shows this could act as a universal therapy."


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