Existing multiple sclerosis therapies systematically modulate the immune system to dampen its erroneous attack on the protective myelin sheaths around nerve cells, which is the hallmark of the autoimmune disease. But this approach puts patients at a higher risk of infection.
Scientists at Thomas Jefferson University said they have found a way to train the immune system to tolerate self-antigens that trigger inflammatory responses in MS while leaving the rest of the immune system intact.
They isolated tiny sacs called extracellular vesicles from cells known as oligodendrocytes. The sacs contained myelin antigens, and when they injected those particles into mice, it suppressed MS, according to a new study published in Science Translational Medicine.
Because existing MS therapeutics suppress the immune system in a systemic way, scientists have been trying to find alternative therapies that target the disease in an antigen-specific way. This approach requires understanding which myelin self-antigens are involved in MS. Problem is, disease-causing antigens can differ among patients or change over 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,” Abdolmohamad Rostami, M.D., Ph.D., the study’s senior author, explained in a statement. “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 and colleagues sidestepped the need to pinpoint specific myelin antigens by turning to oligodendrocytes, which produce the myelin sheath. The team showed that oligodendrocytes produced extracellular vesicles that contained almost all the relevant myelin antigens.
“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,” Rostami said. “It covers all the bases.”
The team tested the vesicles’ efficacy in three MS mouse models representing chronic and relapsing-remitting disease. The drug ameliorated clinical disease both when injected before symptoms developed and after disease onset.
The treatment tamped down the population of infiltrating CD45+ and CD4+ T cells in the central nervous system, the researchers found. The infused vesicles were preferentially taken up by some white blood cells, including monocytes and neutrophils. And the monocytes that absorbed the vesicles pumped up the expression of several anti-inflammatory molecules, such as PD-L1 and IL-10, further helping suppress MS.
The effects of the therapy depended solely on myelin antigens but not other components on the vesicles, the researchers showed. Human embryonic kidney cell-derived vesicles didn’t have any therapeutic benefits and didn’t decrease the number of CD4+ T cells, but genetically edited versions that expressed myelin oligodendrocyte protein did.
Oligodendrocytes’ role in myelin formation was previously leveraged in another way by researchers at the University of Rochester Medical Center to treat MS. That team used human glial progenitor cells to generate new oligodendrocytes, which restored myelin in mouse models of MS.
In another study aimed at replacing destroyed myelin in MS, a team from the VA Maryland Health Care System and the University of Maryland School of Medicine found that some CD34-expressing stem cells can transform into oligodendrocytes.
Rostami’s team at Thomas Jefferson University also isolated the vesicles from human oligodendrocytes and confirmed that they contained therapeutically relevant myelin antigens. The researchers are working on patenting the approach, which they hope will advance toward clinical trials.
“This is a huge advantage of our antigen-specific method over current therapies, which are like a sledgehammer to the immune system, and what makes it so novel,” Rostami said.
by Angus Liu
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