Promising Autoimmune Research: Developing Immune Tolerance

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Promising Research: Developing Immune Tolerance to self-antigens in tackling autoimmune disease

Jasmin Fox-Skelly is a freelance science journalist based in Cardiff, UK

-excerpt New Scientist March 2025

Rather than inhibiting or killing immune cells, (immune suppression) these aim to boost immune tolerance. Pere Santamaria, for example, is developing a new class of nanomedicines called Navacims. These tiny particles reprogram a class of T-cells that, in many autoimmune conditions, are the ultimate source of the problem.

The cells in question, T follicular helper cells, are found in the spleen, tonsils and lymph nodes, where they help B-cells make antibodies against pathogens. However, in many autoimmune diseases, including rheumatoid arthritis, the T follicular helper cells malfunction and encourage B-cells to produce antibodies against a self-antigen. These antibodies act like beacons, drawing an army of white blood cells to the site, which then act on the signal and attack body tissue.

The Navacims can halt this process. They are coated with the self-antigen being targeted, which means they are recognised by the rogue T follicular helper cells. But the Navacims are present in such unnaturally high concentrations that the T follicular helper cells become overwhelmed. This has the surprising effect of prompting them to transform into a totally different type of cell, known as regulatory T-cells, which suppress rather than promote an immune response. “The Navacims can reprogram those aggressive cells and turn them into protectors,” says Santamaria.

Once reprogrammed, the regulatory T-cells multiply, eventually forming an army of white blood cells that ease autoimmunity-triggered inflammation. Because these cells only travel to sites of inflammation associated with the self-antigen, they have a localised effect, while the immune system in the rest of the body continues its job of fighting off infections and cancer.

So far, Navacims have been shown to be effective in animal models of liver autoimmune diseases, type 1 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. A phase I human trial is now under way for autoimmune diseases of the liver.

And speaking of the liver, the organ is at the centre of perhaps the most exciting approach to tackling autoimmune conditions. The liver sits at a crucial position in the body, functioning as a junction between the gut and the blood system. Eighty per cent of the blood entering the liver comes from the gut and, significantly, that blood is full of antigens from broken-down food and gut bacteria. In addition, the liver is also where old, damaged blood cells are sent for disposal – a process that releases even more self-antigens into the bloodstream. To stop all these antigens from sending the immune system into overdrive, the liver has evolved to be an easygoing place. “When antigens are detected there, the immune response is biased more towards tolerance,” says Jeffrey Hubbell at New York University.

Inverse vaccines

Once antigens are detected in the liver, a special type of immune cell, known as an antigen-presenting cell, displays them to T-cells. Elsewhere in the body, this is an important part of the typical immune response and can result in a desired attack, but in the liver, the immune system responds by generating regulatory T-cells – similar to those that Navacims help produce. And just as in the Navacim approach, these regulatory T-cells dampen down the inflammatory response.

Hubbell wondered if he could take advantage of this process to design a kind of “inverse vaccine”. Unlike normal vaccines, which teach the immune system to recognise and attack an antigen associated with a particular pathogen, an inverse vaccine does the opposite: it erases the immune system’s memory of a self-antigen that is triggering an autoimmune response.

The inverse vaccine designed by Hubbell and his team works by attaching the self-antigen in question to a polymer. The polymer is also coupled to a sugar molecule known as N-acetylgalactosamine, which is similar to those found on fragments of old cells, so the body sends the polymer to the liver to be cleared away. Once there, the antigen-presenting cells and regulatory T-cells ensure that the selfantigen on the polymer is recognised but tolerated by the immune system.

In a 2023 study, Hubbell and his colleagues used the approach to treat mice with a multiple sclerosis-like disease. In multiple sclerosis, rogue T-cells attack myelin, an insulative coating surrounding neurons, leading to progressive weakness and numbness, and potentially paralysis and death. To create the inverse vaccine, the team linked myelin proteins to the polymer. In mice given the treatment, the immune cells stopped attacking myelin, allowing the neurons to recover and function correctly.

Significantly, this reduced levels of inflammation – and symptoms of disease in the mice began to reverse. “The reason we were so excited about our results is that we saw a real therapeutic effect,” says Hubbell. “You could take animals that were a full-on immune mess and improve their symptoms with just one course of treatment.”

A phase II clinical trial using a similar technology and concept is currently being carried out in people with coeliac disease, an autoimmune condition associated with an intolerance to gluten, with a phase I safety trial also underway in people with multiple sclerosis. The trials are being conducted by Anokion SA, a pharmaceutical company based in Switzerland that Hubbell co-founded.

Meanwhile, German biotech firm BioNTech is exploring whether the mRNA technology that proved so successful against covid-19 could help tackle autoimmune diseases. Here, the idea is to use mRNA to increase the production of regulatory T-cells for a particular self-antigen, with the aim of teaching the body to avoid attacking it.

Therapeutic approaches based on the production of regulatory T-cells have one key advantage over other approaches: they don’t require you to treat – or even to understand – all the causes of a particular autoimmune condition. This is important because, although an autoimmune condition may begin with an attack on just one self-antigen, as time goes by, the assault broadens and involves many of them. Crucially, however, regulatory T-cells that target just one self-antigen can dampen down the inflammation associated with all of them. “The exciting thing about regulatory [T-cell] approaches is that they have the potential to suppress immunity to antigens that you don’t know exist and that you may never know exist,” says Hubbell.

With so many therapies in development, it looks like the 50-year quest to restore the body’s tolerance for its own tissues is finally nearing its end. Santamaria is cautiously optimistic that one day soon, teenagers diagnosed with conditions like myasthenia gravis will be able to take treatments that allow them to live a normal life, without raising their risk of infection and cancer.

“Of course, we need to carefully advance these treatments through clinical trials to ensure safety and proof of concept, but from what I have witnessed in many animal models of autoimmune disease, I know there is a path forward to tame these diseases,” he says. “I am very hopeful.”