Hope springs eternal: From the New Scientist, latest advances

Arthuritis

Resetting the immune system

says Jasmin Fox-Skelly 

In autoimmune conditions, the body attacks itself, with devastating results. But a raft of therapies that hit the reboot button promise lasting help

PERE SANTAMARIA was 15 when he developed myasthenia gravis. This autoimmune condition causes extreme muscle weakness and can sometimes lead to breathing difficulties. In Santamaria’s case, it affected the ocular muscles controlling his vision, making him see double. 

“It had a tremendous effect on me personally,” he says. “I was becoming an adolescent, and all of a sudden I couldn’t play sports and I couldn’t live a normal life. I had to take very high doses of corticosteroids, which made me swell up like a balloon.” 

Worse, these drugs only dampen down the body’s general immune response, rather than addressing the causes of autoimmunity, meaning Santamaria had no expectation that taking them would ever cure his condition. 

As the years passed, Santamaria developed additional autoimmune conditions – and a determination to learn more about them. “I just wanted to understand the diseases and mechanisms, with the hope I could eventually help others,” he says. 

He has now made progress towards that goal. Working as an immunologist at the University of Calgary in Canada, Santamaria is at the forefront of a push to develop new therapies to reprogram the immune system and encourage the human body to end its destructive war against its own tissues. 

As those therapies move into clinical trials, there are promising signs. Indeed, some are so effective that a single dose has, in a few cases, left people symptom-free for years. So is the end of autoimmune conditions now in sight? Our bodies have several lines of defence against pathogens. Physical barriers like the skin make it difficult for bacteria and viruses to access our internal tissues – and if they do, immune cells such as macrophages can make short work of the invaders by engulfing and digesting them. Such defences form part of our innate immune system, which is a relatively crude but effective way to deal with threats. “They just non-specifically kill the bad guys who don’t look human,” says Daniella Schwartz at the University of Pittsburgh in Pennsylvania. 

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But there is another, far more sophisticated branch of the immune system. Called the adaptive immune system, it is controlled by highly specialised white blood cells known as Band T-lymphocytes. These B-cells and T-cells recognise molecules –known as antigens –on the surfaces of viruses and bacteria, ultimately using this information to destroy the threat. What’s more, Band T-cells can remember antigens, allowing them to respond quickly if they encounter a particular pathogen again in the future, which is the basis of vaccination. 

“Many patients don’t encounter a relapse or a flare-up of their original condition”

Although this makes the adaptive immune system a powerful tool for fending off infections, it can also inadvertently cause problems. Some Band T-cells recognise “selfantigens” – the molecules present on our own cells. Usually, they are programmed to tolerate them, but sometimes they begin to attack those cells instead of pathogens. The result is an autoimmune condition. “Any arm of the adaptive immune system can go wrong and lead to autoimmunity,” says Schwartz

For example, the main cause of lupus – a potentially life-threatening condition that causes inflammation and damage to the skin, joints, heart, lungs, kidneys and brain – is dysfunctional B-cells that produce antibodies against a person’s own DNA. Type 1 diabetes, meanwhile, begins when T-cells attack the insulin-producing cells in the pancreas. 

It is still unclear exactly what triggers autoimmune conditions. “At the moment, they are thought to be the result of interactions between genetic and environmental risk factors, and those vary from person to person,” says Frederick Miller, former head of the Environmental Autoimmunity Group at the National Institutes of Health in North Carolina. 

We do know that autoimmune conditions typically don’t arise overnight. Instead, says Miller, they seem to develop over years – or even decades – from the complicated interplay between risk factors. The resulting conditions can be extremely debilitating. “These are diseases that consume you,” says Santamaria. “They have a devastating impact on patients and their families.” 

Traditional treatments that dampen down all immune activity – such as the one Santamaria was placed on – can ease symptoms. But they do so at a price. “The treatments work fairly well, but they increase the risk of infections and cancer in the long term because they basically suppress your entire immune system,” he says. 

Because of this, it would be preferable 

to somehow restore the body’s tolerance for its self-antigens, either by eliminating or reprogramming the rogue immune cells responsible for autoimmunity. After 50 years of research towards this goal, there are signs it could finally be in reach. 

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For instance, CAR-T(chimeric antigen receptor T-cell) therapies, which have already proved successful at beating some blood cancers, are showing promise as a treatment for lupus. This version of CAR-T therapy involves harvesting T-cells from an individual with lupus before growing and engineering them in a lab so that they express a special protein receptor known as a CAR. The cells are then re-infused back into the individual, where they recognise and destroy B-cells, including those that are the main cause of lupus. The body then produces a replacement population of B-cells, making this therapy a bit like hitting the reset button on the immune system, restoring it back to its factory settings. 

What makes CAR-T therapy so exciting, says Schwartz, is that – in some people – it seems to have a permanent effect. “The therapy depletes a big chunk of the B-cells and it looks like the [lupus-causing] reactive B-cells, for whatever reason, don’t grow back,” she says.  

In a study published in 2022, researchers gave CAR-T therapy to five people with severe lupus. All five experienced remission and were able to stop taking their usual medication – such as the immunosuppressive drug mycophenyolate. According to Georg Schett at Friedrich Alexander University in Germany, who led the clinical trial, some of the participants remain symptom-free today, almost four years after receiving just one infusion of CAR-T therapy. “The immune reset is extremely effective, which makes sense because it isn’t easy to build up an autoimmune disease from scratch, and several checkpoints need to be passed to trigger the disease,” says Schett. “The same process does not seem to happen again. That’s why [many] patients do not encounter a relapse or a flare-up of their original disease.”

Temporary wipeout 

On the back of these promising results, Schett and his colleagues have begun a clinical trial involving people with several other autoimmune conditions. CAR-T therapy for lupus is also now the subject of a phase I clinical trial led by University College London and the University College London Hospitals NHS Foundation Trust, where the aim is to assess safety and establish effective doses in a small number of people with the condition. 

Such trials are vital because CAR-T therapy can cause serious side effects – it can even lead to death from infection after B-cells have been wiped out. Furthermore, the long-term impact of deleting those immune cells – albeit temporarily – is unknown. CAR-T therapy is also expensive, with each infusion costing an average of more than $600,000. “I think we’re still going to see these as rather expensive treatments that maybe not all patients will have access to because of the cost,” says Miller. 

The good news is that other, potentially cheaper and safer treatments are in the pipeline too. Rather than inhibiting or killing immune cells, these aim to boost immune tolerance. 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.

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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. 

“ The 50-year quest to restore the body’s tolerance to its own tissues is finally nearing its end”

the blood is passed through a centifuge before being genetically modified

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.” 

-For further info, see this week’s New Scientist.

Eeyore

Hello @Arthuritis

Thank you so much for posting this, very, very interesting. There is hope - of course it will take a few years before anything concrete comes of this research and I'll probably have popped my clogs before then but so good to know that possible cures are being investigated which could improve the lives of so very many people.

frogmorton

Have you seen the latest Zoe podcast by Dr Tamiko Katsumoto @Arthuritis ?

You must have a listen/watch.

Thanks for the above BTW as usual really interesting.

Toni x

Arthuritis

I hadnt, so thank you so much, I listened to it, https://podcasts.apple.com/gb/podcast/zoe-science-nutrition/id1611216298?i=1000696532853

It’s great that it’s starting to consider getting off meds and not condemning patients to them forever. However their study does not baseline what the participants actually ate before the study, or what exact medications were dropped. A typical American diet compared to ours are highly inflammatory, so I can see how moving to a Whole Foods Plant (not american meat) based diet would make a profound difference, and for those on a particular spectrum of chronic meds the change may be enough to put them into remission.

While I like plant based food, the health benefits are not from plants alone, but from avoiding things that your gut immune system seems as inflammatory. I wholly agree with her assertion that they feel their joints react to trigger foods when they have transitioned to remission, that happened to me, but the triggers were surprising:

cherries

avocados from a high end supermarket (Tesco was fine)

papaya

Chicken/poultry

salmon

cheeses except goat cheese

any fish

However McDonald’s Big Mac had NO adverse impact on my joints, but fine salmon & sushi did put my joints on fire. The amount of the fireworks food eaten matters. The BigMac experience prompted me to think beef was the only safe protein I could have, which was true, except raw beef as in beef tartar, that bumped me out of remission with just 3 tiny taco “boats” as a starter.

https://stanfordhealthcare.org/trials/t/NCT05678075.html

I take things from Stanford with a pinch of salt though (!) … as I wonder about how much they benefit from big industry donations, and rely on their brand. That said, I agree that if your starting point is a rubbish processed food sugary toxic diet, then WFPBD would be of great benefit, even enough to get you off meds. However your health foods as I found, may themselves be a trigger - see my own list of forbidden foods, even during remission. It’s not necessarily how healthy it is in general, but how your specific misguided gut immune system reacts to it. Remember I had no reaction to a BigMac! The only pattern I noticed was that during covid I ate everything on my prohibited list, after RA diagnosis I could only eat them while on max MTX, but during remission without MTX, the only proteins I could have was those that I did NOT normally eat (Goat cheese, beef/red meat). Beans were an absolute no-no, they triggered a flare even on MTX, and had to increase my MTX from 20mg to 25mg max.

So the only sure thing from the podcast is that some people may be able to induce remission if they carefully filter out their trigger foods and don’t assume there are any “healthy angel” foods, as in my case, even lovely avocados triggered joint pain, as did cherries, papaya and some apples, all beans. The remission induction exists if their inflammatory state is being maintained by constant trigger food presence. This does not happen if it’s a self sustaining inflammation loop (I think this is in the brain - Dr Kevin Tracey Neurosurgeon).

Trish9556

Thanks @Arthuritis

Definitely gives me something to think about.

Trish xx