Your immune system has a great memory, and it keeps an enemies list.

Which is helpful when it remembers viruses like the ones that cause COVID or the flu and kicks them out on their little virus butts. It's less helpful when it adds your own pancreas to that enemies list, and suddenly you have type 1 diabetes.

Same goes for any other autoimmune disease. That's why we'd really like a way to selectively edit that enemies list. And scientists are working on a vaccine that does the opposite of what most vaccines do: it will make your immune system forget. [♪ INTRO] Your immune system has superpowers, like the ability to tailor its response to threats.

Specialized cells remember threats they’ve seen before and go after only that, and not other stuff. Otherwise getting sick might be a lot more miserable. It does this through T cells, as well as the antibodies produced by B cells, both of which are able to recognize and target specific antigens.

Antigen refers to anything that can stimulate the immune system to create antibodies – whether or not a response is actually needed. Unfortunately, sometimes immune cells pick the wrong target, such as the proteins made by your own cells. This response to normally harmless self-antigens is what leads to autoimmune diseases.

Jerks of the “your own body attacking itself” variety include multiple sclerosis, celiac disease, and type 1 diabetes. Currently, one way of treating autoimmune disease is with immunosuppressive drugs. They work in a few different ways but in general, they tamp down immune activity across the board.

Meaning the patient’s autoimmune symptoms might improve, but in exchange, they’re more vulnerable to infection and even cancer. So, not ideal. Thankfully, treating autoimmunity with targeted tools is an active area of research.

One possible solution is backwards or “inverse” vaccines. In a paper published in 2019 in Nature Biomedical Engineering, researchers based in the US and Switzerland hypothesized that they could use the liver to tell the immune system to shut up, it’s fine, everything’s fine here. Kind of like me yelling at the fire alarm after I burn something in the oven.

Their strategy would enable selective immune forgetting, rather than relying on global immune suppression. Covid, keep. Pancreatic cells, delete.

Measles, definitely keep. It would theoretically work because the liver plays a huge role in immune decision-making. This is because the liver is involved in filtering blood and breaking down toxins, but also debris from dead cells.

It happens, right? Cells die and somebody’s gotta clean ‘em up. If the liver can handle a molecule, there’s no need to mount an immune response, so it gets to judge which molecules your immune cells see as dangerous or innocuous.

This process relies on regulatory T cells. Instead of attacking, these T cells calm things down and help the body remember that a particular antigen is no big deal. Proteins released from dying cells have specific tags on them made of sugars.

The sugar tags are these molecules or pGlu and pGal for short. These tags are sort of like shipping labels directing those antigens to the liver. There, they get processed by cells in the liver that talk to the immune system.

And what those cells are saying is “this lives here, it’s ok.” So a pGlu or pGal tag should, in theory, make an antigen head straight for the liver, where it should run into the immune system in a nice, safe, “everything is ok here” kind of context. In order to test this idea, researchers injected mice with a protein from eggs called ovalbumin to kinda give them an egg allergy. Sometimes the ovalbumin had the sugar tags, and sometimes it didn't.

They also gave the mice a bunch of T cells that they could easily follow, in order to track the mice's immune responses. When they followed up a week later, they found that the number of ovalbumin-specific T cells in the liver was higher in the mice who’d gotten tagged ovalbumin. That suggested the tags were helping the liver recognize ovalbumin as harmless.

T cell numbers were /higher/ in the tagged group, but this didn’t mean those mice were having an enhanced immune response. These were regulatory T cells, the “calm down” T cells I mentioned earlier. So, alright.

We can use sugar tags to prevent a fake egg allergy, but can we do this with something more closely resembling a real disease? The researchers turned to a mouse model of type 1 diabetes, in which T cells are programmed to recognize insulin-producing cells in the pancreas. Recognize, and attack.

If these T cells are injected into a mouse, they tend to go into seek and destroy mode. Those T cells are going after an antigen called p31. So, the mice first got injected with these T cells.

On the same day, they were injected with p31 with and without sugar tags. Mice that got p31 without a sugar tag very quickly developed high blood sugar. However, in the mice that were vaccinated with p31 plus a pGlu tag, the immune system was able to prevent glucose levels spiking, even in the presence of the attack T cells.

The researchers showed this was because the attack T cells weren't attacking. Basically, the vaccine was able to train the T cells that recognized p31, showing them that the liver thought everything was fine. That taught the T cells that they could chill out, transform into regulatory T cells, and let the pancreatic cells get on with producing insulin.

Basically, the inverse vaccine kept the mice from developing type 1 diabetes for a long time, even though they were prone to it. But that’s not what you’re typically going to run into in the real world. Usually, when a patient goes to their doctor, it’s with an autoimmune disease already in progress.

So the question becomes whether this approach works as a cure, not just prevention. In another paper in 2023, the research group published results demonstrating the strategy worked for treating mice who had a mouse version of multiple sclerosis. In multiple sclerosis, the insulating layer around nerve fibers, called myelin, is attacked by the immune system.

Vaccinating mice with myelin tagged with pGal decreased MS symptoms and calmed down their overachieving T cells. They also showed the pGal-tagged vaccine strategy worked to suppress immune response in a nonhuman primate, another step closer to showing efficacy in humans. Even better than that, a few early human trials employing the sugar tag inverse vaccine approach are already happening.

A phase I trial for an inverse vaccine for celiac disease has already wrapped up, and a phase I trial for multiple sclerosis is in progress at time of filming. Phase I trials are super early. They mostly just prove that a therapy is safe to give to humans, not whether or not it works.

Still, you love to see it. Vaccines have revolutionized the fight against disease by helping our immune systems learn to recognize threats before they occur. Inverse vaccines could be the way we teach our immune systems to forget.

Forget to give us a hard time. Which sounds like another huge step to me. You know who helps our channel make huge steps in communicating awesome science to the world?

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If you’d like to join our amazing community, you can get started at patreon.com/scishow. [♪ OUTRO]