Multiple sclerosis (MS) is an autoimmune disease that occurs when the body responds to its central nervous system and mounts an immune attack, using T cells against its myelin—the protective coating around nerve cells—and the oligodendrocytes that produce myelin. This leads to scar tissue, degradation of nerve fiber, and eventual loss of motor function. Thus far, MS has typically been treated systemically with drugs that suppress the entire immune system, which causes a host of side effects, including susceptibility to infection, hair loss, bladder infections, and nausea, among others.
Now, a team of researchers from the University of Maryland (UoM), has formulated a new therapeutic approach in mice that focuses on a specific immune target—the lymph nodes—without causing systemic immune suppression. Using this technique, they reversed MS-like paralysis in mice. Lead researcher Christopher Jewell, assistant professor of bioengineering at UoM, presented their findings yesterday at the 253rd National Meeting and Exposition of the American Chemical Society. These new results are a continuation of research the team published in the September 2016 issue of the journal Cell Reports.
Jewell tells mental_floss that you can think of the lymph nodes as the place where immune cells are assigned their jobs. The lymph nodes program these cells to differentiate—that is, they tell the cells whether or not they will become inflammatory cells that cause disease, or regulatory cells that control disease. To limit the immune suppressing effects of a systemic injection, Jewell’s team tested a local effect by injecting custom-designed particles made of biodegradable polymer and loaded with immune signaling molecules directly into the lymph nodes of mice.
“We make these polymer particles too big to drain out of the lymph nodes,” Jewell says. The particles slowly degrade and release these immune signaling molecules “that program the immune cell there to have the function that we want—in this case, immunological tolerance.”
The polymers are loaded with two well-studied molecules in the field of MS treatment: peptides derived from myelin cells, and an immunosuppressive drug called rapamyacin. When the T cells in the lymph nodes encounter the molecules embedded in the polymer, “they go to the brain and calm down the cells there that are causing an attack.” Jewell says. This is "a very selective way to block incorrect immune function.”
CAUSING PARALYSIS IN ORDER TO REVERSE IT
To test these effects, they used a well-established model to induce the disease symptoms of MS in mice: They injected myelin and an inflammatory molecule into healthy mice to activate the T cells to attack myelin. About 10 to 12 days later, the mice start to lose motor function in their tails and hind limbs. "Eventually they become quadriplegic,” Jewell says.
Once the mice were effectively paralyzed, the researchers made a one-time injection of the myelin/rapamyacin polymer bundle into the mice's lymph nodes, then monitored the animals every day after. “They gradually regain function over about a week or two,” says Jewell. First they began to walk, then could stand on their hind limbs, and eventually they regained full function of all limbs. Some mice didn't regain full function of their tails, but the results nevertheless indicate the treatment had “a massive therapeutic effect,” Jewell says.
The reversal of paralysis lasted as long as the duration of the experiments, which was up to 90 days in some groups of mice, and he has confidence it may be a permanent effect.
CAN THE IMMUNE SYSTEM STILL DO ITS JOB?
In addition to this research, Jewell presented new results from ongoing experiments in which they are studying whether the MS-induced mice that recovered from paralysis were immunocompromised—meaning that their immune systems could no longer fight foreign invaders. Once the mice's recovery from paralysis seemed stable, the researchers immunized the mice with a foreign peptide, ovalbumin, commonly used as a model antigen because it’s easy to track the T cell response for ovalbumin. Each week they monitored the generation of ovalbumin-specific T cells by drawing blood samples. “We’ve shown they can mount specific responses to these antigens, which shows the mice are not immunocompromised,” Jewell says.
This was one of the key goals of doing the local lymph node injections, since current treatments for MS all suppress the entire immune system. To test this result further, they will soon conduct studies in which mice that recover from paralysis are challenged with common pathogens that healthy mice can overcome. “Hopefully we’ll see that these mice can also overcome that, confirming in a more functional way that they are not immunocompromised,” Jewell says.
TESTING THE TREATMENT'S POTENTIAL FOR DIABETES
Even more exciting to Jewell is that they're using this same localized approach to investigate its potential for other autoimmune diseases. In one study currently underway, they have loaded the polymers with pancreatic islet cells and rapamyacin to test the therapy in diabetic mice. “We’re getting good results," he says. "If mice are diabetic and we treat them, they are able to maintain their blood glucose and survive longer than the mice we didn’t treat.”
All of this research adds up to promising potential therapeutics, for MS and other autoimmune diseases, that don’t suppress the immune system. In fact, this approach is being called an “inverse vaccination”—a term coined by Stanford neurologist Larry Steinman. “It’s a vaccination that’s trying to turn off the immune system,” Jewell explains. “We’d like to turn off the part of the immune system that’s functioning against MS, but not the flu, for example.”
They’ll begin non-human primate studies later this year. Before they can move to human clinical trials, Jewell says they need to prove that the no-longer-paralyzed mice aren’t immunocompromised, as well as to test their hypothesis that the reason the mice start walking again is that remyelination is occurring—in essence, that the central nervous system is regrowing the damaged myelin.
Ultimately, he feels that their research adds to a growing field of study that benefits from such a multidisciplinary approach. “You have to have the confidence that some strategy will be better for autoimmune disease,” he says.