IMMUTOL: Reprogramming immunity to move beyond management towards a cure for autoimmune disease

For decades, the treatment of autoimmune disease has focused on managing symptoms rather than treating the cause. Therapies have been developed to suppress immune activity, control symptoms, and slow disease progression, often with meaningful benefits for patients, but rarely offering a lasting solution. The IMMUTOL project takes a different approach. Rather than dampening the immune response, it aims to retrain it.

“At the moment, all the treatments that are applied to patients with an autoimmune disease like multiple sclerosis are focused on controlling the symptoms, but not the real cause of the disease,” explains Dr. Silvia Gregori, Head of the Mechanisms of Peripheral Tolerance Unit at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), and coordinator of the project. “So, despite the treatment patients receive, the disease still progresses. It may be delayed, but it is not stopped.”

This distinction between control and cure is not just a clinical one. It shapes how the disease is experienced day to day. While treatments may slow progression, they do not remove the underlying risk, leaving patients living with the uncertainty of complex, long-term conditions. Over time, treatments evolve, often losing effectiveness, requiring patients to switch approaches while managing side effects that can be as disruptive as the disease itself.

“Patients take the medication, but they are not satisfied,” Gregori explains. “Treatments control the disease, but patients have other symptoms, and what many tell me is that they know they are not cured.”

“This is difficult for them, particularly for younger patients,” she continues. “There is a persistent sense that the disease may worsen, even under treatment, and so they live with something on their shoulders, never knowing when the disease may progress.”

“This reality of partial control combined with long-term uncertainty has created a space for new approaches like the one under development in IMMUTOL, which is looking not simply for better drugs, but for fundamentally different strategies.”

A broken balance
At its core, IMMUTOL builds on a simple principle of how the immune system is meant to function. In healthy individuals, the immune system balances the need to respond to threats with the ability to stop that response at the right time. It can react aggressively to threats, but just as importantly, our immune system knows when to stop and switch off. In autoimmune disease, that balance breaks down.

“The immune system is educated not to attack our own tissues,” Gregori explains. “In patients with autoimmunity, the mechanisms that control the immune homeostasis are broken, and the result is a sustained immune attack against the body’s own cells – myelin in MS, insulin-producing cells in type 1 diabetes, joints in rheumatoid arthritis.”

“What we propose in IMMUTOL is not to suppress this attack, but to restore the balance that prevents it,” she continues. “If we can reinstall the balance, then the natural mechanisms will be reactivated, and the patient can be cured in the longer term.”

Re-educating the immune system
To restore that balance, IMMUTOL turns to one of the immune system’s most influential cell types: dendritic cells. These are the cells that decide how the immune system responds – whether to trigger an attack or to hold back. “They are critical for both the activation and the regulation of the immune response,” Gregori explains. “If you have an infection, dendritic cells activate the immune system. But they are also responsible for switching it off.” In autoimmune disease, the ability to restrain the response no longer works as it should. IMMUTOL’s approach is to rebuild it. “The idea is to generate these cells in vitro, educate them to be regulatory, and then reinfuse them into the patient,” she says.

That “education” process is central. Cells are taken directly from the patient’s blood and guided, outside the body, into a state where they promote tolerance rather than attack. This is achieved using a combination of biological signals, most notably vitamin D3 and interleukin-10. “Vitamin D3 has already been used to generate tolerogenic dendritic cells,” Gregori notes, referring to earlier clinical trials. “In IMMUTOL, we combine this with interleukin-10 to make these cells even more strongly regulatory.”

The result is a cell designed not to suppress the immune system broadly, but to recalibrate it – to reintroduce the signals that control it. Crucially, these are not donor cells or synthetic constructs. They come from the patient themselves. “We use the same cells of the patient,” Gregori explains. “We generate them from circulating monocytes, educate them, and then reinfuse them in an autologous setting.”

This autologous approach avoids the risk of rejection and allows the therapy to work with the patient’s own immune system, rather than against it. It is personalised in the most practical sense: each treatment is created individually from the patient’s own cells. “What we are attempting, then, is not to override the immune system, but to remind it how to function as it was originally intended – restoring a balance that has been lost.”

From concept to clinic
Translating this approach from lab success into a treatment that patients can use is another demanding challenge the project faces. Developing a cell-based therapy involves not only demonstrating biological efficacy but also navigating a rigorous pathway of validation, manufacturing, and regulation. The project is now well advanced along that road. “We have generated the new product, validated it in vitro, and performed in vivo studies in preclinical models,” Gregori explains.

The next phase focuses on scaling up production under Good Manufacturing Practice (GMP) conditions, a critical step in preparing the therapy for clinical trials. Yet even here, the challenges are substantial. Unlike conventional pharmaceuticals, these are living therapies produced individually for each patient. “Production is patient to patient,” she says. “The procedure is the same, but we need to produce the cells for each individual, and this introduces both logistical and economic challenges. It is this complexity that will ultimately shape how widely therapies like these can be deployed.”

If successful, the implications of this approach could be profound. The immediate goal is to stabilise disease progression and reduce reliance on existing medications. Over time, however, the ambition is to eliminate the need for treatment altogether. “The best outcome would be that patients can gradually reduce their medication and eventually no longer need it at all,” Gregori says. “At that point, you are no longer managing the disease – you are effectively curing it.”

“There are limits to what can be reversed, particularly in diseases like MS, where tissue damage accumulates over time,” she continues. “But even halting progression would represent a major advance.”

Looking further ahead, Gregori believes the greatest potential in this work may lie in intervening much earlier in the disease process. “The best outcome would be to treat the patient before the onset of the disease,” she says. “If we can restore tolerance at that stage, we could stop the disease before any damage occurs. That would mean moving away from treating symptoms and progression, towards preventing the disease altogether.”

Patient response
One of the most striking aspects of IMMUTOL is not only the science itself, but the response it has generated among patients. Despite the complexity of the process and the fact that the therapy involves genetically modified cells, there is a clear willingness to engage. “I was completely surprised,” Gregori admits. “Patients said to me, if there is this kind of approach tomorrow, I will take it.”

For her, this response reflects the limitations of current treatments. “Patients are not simply looking for better ways to manage their condition; they are looking for something more,” Gregori explains. “They are looking for something that offers the possibility of resolution rather than control, and they are open to new therapies that may finally give them that hope to be cured.”

What emerges even more strongly, however, is a broader perspective on what this kind of research represents. Many patients recognise that therapies like IMMUTOL will take time to reach the clinic, and that they themselves may not ultimately benefit.

Yet that does not diminish their support. “They are not really focusing on themselves, but on the whole community,” Gregori observes, suggesting a willingness by sufferers to support progress that may ultimately only help others and not necessarily themselves.

The cost of innovation
For all its promise, the path to real-world impact for IMMUTOL will not be defined by science alone. One of the most significant barriers facing IMMUTOL, and cell therapies more broadly, is the expense of production. Overcoming this barrier will require more than scientific progress alone. It will demand changes in how these therapies are funded, regulated, and brought to market, areas where European institutions have a critical role to play.

For Gregori, the challenge lies in the cost and complexity of bringing this type of therapy into real-world use. “The manufacturing cost is very, very high,” she says, pointing to the realities of producing personalised, cell-based therapies under strict regulatory conditions. That cost creates a disconnect between scientific progress and investment. “When you start to discuss with venture capital, as soon as they hear about ex vivo cell therapy, they say the cost is too high,” she explains.

Bridging that gap will require sustained engagement between researchers, regulators, and policymakers. Gregori points to ongoing discussions at the European level – particularly in fields such as gene therapy – where there is growing recognition that development pathways and cost structures may need to evolve if these treatments are to reach patients. “We need to continue the discussion with regulatory authorities and the European community,” she says, “to find the right way to allow people to access these kinds of therapies.”

A platform for the future
While IMMUTOL focuses on MS, its implications extend far beyond it. “The approach can be easily transferred to other autoimmune diseases,” Gregori says, pointing to a wider field of conditions driven by the same underlying immune response imbalance. In that sense, MS serves as a valuable proving ground for the therapy and a way to demonstrate that immune tolerance can be restored in practice. “If that can be shown, the same principle could then be applied across a range of diseases,” Gregori says. “We can treat many diseases, from type 1 diabetes to rheumatoid arthritis, where current treatments still revolve around long-term management rather than resolution.”

For Gregori, however, this is not a standalone advance limited to autoimmune disease, but part of a broader shift already underway within the field. Researchers across Europe are working collectively to refine and extend these approaches, building a foundation for therapies that do more than suppress disease. “We are all working together in this direction,” she says. “There is a growing community focused on making cell-based immunotherapies viable across multiple indications.”

There are still significant barriers to overcome, particularly in cost and manufacturing, but the trajectory is becoming clearer. IMMUTOL is part of a broader effort to change what treatment means in autoimmune disease. “If we are successful in this, the long-term impact will not simply be better ways to manage these conditions, but the possibility of restoring the balance that prevents them from developing in the first place.”