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Rebooting the immune system in MS patients

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Every day, someone in Switzerland is diagnosed with multiple sclerosis. Multiple sclerosis is an autoimmune disease in which the body’s immune system attacks the myelin sheath of nerve cells in the brain and spinal cord. The disease causes paralysis, pain and permanent fatigue, among other symptoms. Fortunately, there have been great advances in therapies over the past few decades. A study from the Department of Neuroimmunology and MS Research at the University of Zurich (UZH) and the Department of Medical Oncology and Hematology Clinic at the University Hospital Zurich (USZ) has now identified why most effective therapy currently available – a stem cell transplant – works so well.

Eliminate unwanted immune cells

“80% of patients remain disease-free long-term, or even forever, after autologous hematopoietic stem cell transplantation,” says recently retired Professor Roland Martin, study leader and final author. The treatment is particularly suitable for younger people with aggressive forms of the disease. Four years ago, thanks to the high efficacy of the treatment and the now low mortality rate, Martin’s department and the USZ clinic were granted permission to administer the therapy. It is the only clinic in Switzerland approved for this treatment.

During treatment, many chemotherapies completely destroy patients’ immune systems – including the subset of T cells that mistakenly attack their own nervous system. Patients then receive a transplant of their own blood stem cells, which were harvested before chemotherapy. The body uses these cells to build a completely new immune system without any self-reactive cells.

Systematic analysis of immune cells

“Previous studies have shown the basic workings of the method, but many important details and questions have remained open,” says Martin. Some unclear aspects were what exactly happens after the immune cells are eliminated, if any of them survive the chemotherapy, and if the autoreactive cells don’t really come back.

In the recently published study, Martin’s team systematically investigated these questions for the first time by analyzing immune cells from 27 MS patients who received stem cell therapy in Zurich. The analysis was performed before, during and up to two years after treatment. This allowed the researchers to track the rate of regeneration of different types of immune cells.

Successful reset of the immune system

Surprisingly, cells known as memory T cells, which are responsible for ensuring the body remembers pathogens and can respond quickly to new infections, reappeared immediately after the transplant. Further analysis showed that these cells did not reform, but survived the chemotherapy. These remnants of the original immune system do not, however, present any risk of recurrence of MS: “They are pre-damaged by chemotherapy and are therefore no longer capable of triggering an autoimmune reaction”, explains Martin.

In the months and years following the transplant, the body gradually recreates the different types of immune cells. The thymus gland plays an important role in this process. This is where the T cells go to school, so to speak, and learn to distinguish foreign structures, like viruses, from their own. “Adults have very little functional tissue in the thymus,” says Martin. “But after a transplant, the organ seems to resume its function and ensure the creation of a whole new repertoire of T cells which obviously do not trigger MS or make it come back.”

Further studies needed for broader approval

These findings have allowed researchers to understand why stem cell transplants are generally so successful. But unfortunately, says Martin, the treatment is not approved in many countries because phase III studies are lacking. “Phase III studies cost several hundred million euros, and pharmaceutical companies are only willing to conduct them if they make money afterwards.” This is not the case with stem cell therapy, as the drugs used are no longer protected by patents.

“I am therefore very happy that we have succeeded in obtaining approval for the treatment from the Federal Office of Public Health and that the health insurers are covering the costs,” says Martin. In the past, many Swiss MS patients had to travel to Moscow, Israel or Mexico to receive transplants.

Literature:

Josefine Ruder, María José Docampo, Jordan Rex, Simon Obahor, Reza Naghavian, Antonia MS Müller, Urs Schanz, Ilijas Jelcic, Roland Martin. Dynamics of the renewal of the T lymphocyte repertoire after autologous transplantation of hematopoietic stem cells in multiple sclerosis. Science translational medicine. November 2, 2022. DOI: 10.1126/scitranslmed.abq1693