A blood stem cell transplant could reboot the immune system in multiple sclerosis patients

A blood stem cell transplant could reboot the immune system in multiple sclerosis patients

A blood stem cell transplant could reboot the immune system in multiple sclerosis patients

Abstract: 80% of multiple sclerosis patients remain disease-free long-term after autologous hematopoietic stem cell transplantation.

Source: University of Zurich

Every day one person in Switzerland is diagnosed with multiple sclerosis. MS is an autoimmune disease in which the body’s own immune system attacks the myelin sheath of nerve cells in the brain and spinal cord. The disease, among other symptoms, leads to paralysis, pain and permanent fatigue.

Fortunately, there have been great advances in therapies in recent decades. A study by 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 shown why the most effective therapy currently available – stem cell transplantation – works so well .

Destruction of unwanted immune cells

“80 percent 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 especially suitable for younger people with aggressive forms of the disease. Four years ago, thanks to the high efficiency of the treatment and the now low mortality rate, Martin’s department together with the USZ clinic received approval to carry out the therapy. It is the only clinic in Switzerland approved for this treatment.

During treatment, several chemotherapies completely destroy a patient’s immune system—including a subset of T cells that mistakenly attack their own nervous system.

Patients then receive a transplant of their own blood stem cells that were collected before chemotherapy. The body uses these cells to build an entirely new immune system without any autoreactive cells.

Systematic analysis of immune cells

“Previous studies have shown the basic workings of the method, but many important details and questions remain open,” says Martin. Some unclear aspects were what exactly happens after the immune cells are eliminated, whether any of them will survive the chemotherapy, and whether the autoreactive cells will indeed not return.

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

Successful resetting of the immune system

Surprisingly, cells known as memory T cells, which are responsible for the body remembering pathogens and being able to respond quickly in the event of a new infection, reappeared immediately after the transplant.

Further analysis showed that these cells did not re-form, but survived the chemotherapy. However, these remnants of the original immune system do not pose a risk for MS to return: “They have been damaged in advance by the chemotherapy and therefore can no longer trigger an autoimmune reaction,” explains Martin.

A blood stem cell transplant could reboot the immune system in multiple sclerosis patients
Patients then receive a transplant of their own blood stem cells that were collected before chemotherapy. The image is in the public domain

In the months and years after the transplant, the body gradually regenerates different types of immune cells. The thymus gland plays an important role in this process. Here, T-cells go to school, so to speak, and learn to distinguish foreign structures, such as viruses, from their own.

“Adults have very little functional tissue in the thymus,” says Martin.

“But after transplantation, the organ seems to resume its function and ensure the generation of a whole new repertoire of T cells that apparently do not trigger MS or cause it to come back.”

Further studies are needed for wider approval

These discoveries allowed researchers to understand why stem cell transplants are usually so successful. But unfortunately, Martin says, 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 will make money afterwards.” This is not the case with stem cell therapy because the drugs used are no longer protected by patent.

“So I’m very pleased that we were able to get approval for the treatment from the Federal Office of Public Health and that health insurance covers the costs,” says Martin. In the past, many MS patients from Switzerland had to travel to Moscow, Israel or Mexico to receive a transplant.

See also

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About this multiple sclerosis research news

Author: Kurt Bodenmüller
Source: University of Zurich
Contact: Kurt Bodenmueller – University of Zurich
Picture: The image is in the public domain

Original research: Open access.
Dynamics of T cell repertoire renewal after autologous hematopoietic stem cell transplantation in multiple sclerosis” Roland Martin et al. Science translational medicine


Abstract

Dynamics of T cell repertoire renewal after autologous hematopoietic stem cell transplantation in multiple sclerosis

Autologous hematopoietic stem cell transplantation (aHSCT) is a very effective treatment for multiple sclerosis (MS). It depletes autoreactive cells and then restores adaptive immune cells.

The possible proinflammatory potential of surviving T cells early after aHSCT has not been studied.

Here, we examined the dynamics of new and surviving T cells in 27 patients after aHSCT by multidimensional flow cytometry, T cell receptor (TCR) sequencing, specificity testing, telomere length profiling, and HLA genotyping.

Early after aHSCT, naïve T cells are barely detectable, while effector memory (EM) T cells are rapidly reconstituted to pre-aHSCT values. EM CD4+ T cells early after aHSCT have shorter telomeres, have higher expression of senescence and exhaustion markers, and proliferate less than those before aHSCT.

We find a mean TCR repertoire overlap of 26% between early post-aHSCT EM CD4+ T cells and pre-aHSCT, indicating persistence of EM CD4+ T cells early after transplantation.

EM CD4+ Overlap of the TCR repertoire declines to 15% 12 months after aHSCT, while the naïve TCR repertoire is fully restored. EM CD4 associated with HLA-DR+ T cell reactivity to MS-associated antigens decreased after aHSCT, whereas reactivity to EBV increased.

Our data show significant survival of pre-aHSCT EM CD4+ T-cells early after transplantation, but complete restoration of the T-cell repertoire by nascent T-cells later.

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