Reprogramming the immune system to reverse paralysis
Sometimes, our immune system experiences glitches, causing it to turn against the very cells and tissues it's supposed to protect, leading to an autoimmune disorder or disease. What if, like computers, the immune system could be reprogrammed to restore our body's functions? Scientists at the University of Maryland have done just that with paralyzed mice, using an experimental treatment that might one day reverse the effects of autoimmune diseases, such as multiple sclerosis (MS), in humans.
The body's immune system is assisted by a type of white blood cells known as the T cells, which comprise three different groups: helper T cells, killer or inflammatory T cells, and regulatory T cells. In autoimmune disease, when a body-roaming helper T cell recognizes an antigen – a toxin that triggers the immune system to produce antibodies – it is taken back to the lymph nodes, where the killer T cells are then programmed to attack it. While the exact antigen that triggers MS remains a mystery, what is known is that it develops when the immune system attacks the myelin, the fatty sheath that insulates and protects the nerves in the central nervous system, causing inflammation and damage to the part of the brain that controls movement, resulting in the loss of motor function over time.
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Current immunotherapies for MS tend to have a broad approach that exposes the patient to a range of often potent side effects while targeting the disease.
"The problem with current immunotherapies is that they aren't specific," says bioengineering associate professor Christopher Jewell. "They act broadly, compromising the entire immune system and putting the patient's health at risk, rather than focusing on only those immune system cells doing the damage."
What if there was a way to pre-empt the attack by reprogramming the response of the T cells in the lymph node so that they become regulatory cells, which switch off the immune response, instead? Inspired in part by allergy shots, in which patients are exposed to tiny doses of a specific allergen to build up a tolerance to it, as well as clinical trials involving allergy treatments targeted at specific lymph nodes, Jewell and his team wanted to find out whether they could combine the two approaches and deliver an immune-system modifying agent to the lymph nodes directly.
The researchers did this by designing polymer particles infused with an immune-suppressing agent and the myelin antigen that could be injected directly into the lymph nodes. These were deliberately designed to be too big to drain out of the node so that they would slowly degrade and release signals that would reprogram the response of the immune system cells there, causing them to become regulatory instead of inflammatory cells in the brain. This, says Jewell, targets the problem in a more specific way without affecting the rest of the immune system.
To test the efficacy of the agent, the researchers injected it into the lymph nodes of paralyzed mice with MS. Except for the partial use of their forelimbs, they were unable to move their hind limbs and tail. This situation changed after they were given the treatment, which resulted in the particles reprogramming the response of the T cells lymph node tissues to stop the attack against the myelin. Previously, the mice had to drag themselves by their forelimbs around the cage. Now, they could walk normally and stand on their hind limbs, as well as use their tails.
This lasted for the duration of the study (around 80 days) and what was also promising was that the mice were able to readily respond to the introduction of foreign molecules, which suggests that their normal immune function wasn't compromised by the treatment.
Before this idea can be adapted to treat human patients, more work has to be done to make sure the treatment doesn't leave the immune system vulnerable to other pathogens. At present, the researchers are testing this treatment in other mouse models of autoimmune disease, such as Type 1 diabetes. The goal is to get a better understanding of the mechanisms underlying the immune system and to ensure the mice undergoing these tests have a robust immune system that is comparable to a healthy mouse's. To see how this works in a model that bears some similarities to human beings, the group will also be conducting tests in non-human primates in the future.
The research was presented at the 253rd National Meeting & Exposition of the American Chemical Society. Jewell discusses his lab's work in the video below.
Source: American Chemical Society