Immune ‘Reeducation’ Using Red Blood Cells: First Clinical Trial of a Tolerance Therapy for Multiple Sclerosis

A multiple sclerosis treatment that uses red blood cells to “teach” the immune system has entered clinical testing for the first time.

According to a report by BioOn on the 4th (local time), researchers from the University of Zurich in Switzerland and other institutions published results from an open-label, dose-escalation phase 1b clinical trial of autologous red blood cell-based antigen-specific tolerance therapy in the international journal PNAS.

Multiple sclerosis is an autoimmune disease of the central nervous system that affects about 3 million people worldwide and primarily develops in people ages 20 to 40. Autoreactive T lymphocytes mistakenly attack the myelin sheath in the brain and spinal cord, causing vision loss, sensory loss and paralysis of the limbs.

Existing disease-modifying therapies reduce relapse frequency but use broad immunosuppressive strategies, increasing the risk of infection and malignancy with long-term use. To avoid this limitation, the researchers chemically attached seven immunodominant peptides, including myelin basic protein, to the surface of patients’ own red blood cells and reinfused them.

As these modified red blood cells aged, they were captured and broken down by Kupffer cells in the liver and marginal zone macrophages in the spleen, inducing antigen-specific immune tolerance rather than activating the immune system.

Several patients with relapsing-remitting or secondary progressive multiple sclerosis participated in the trial. Follow-up after a single dose showed no dose-limiting toxicities or serious adverse events, and the Expanded Disability Status Scale scores and magnetic resonance imaging lesion burden remained stable in most patients.

Levels of serum neurofilament light chain, a marker of neuroaxonal injury, decreased. The researchers said this decline suggests that inflammation in brain tissue was partially suppressed.

Single-cell RNA sequencing showed clonal expansion of CD4+ memory T cells with a regulatory phenotype and a reduction in inflammatory effector cells 3 months after treatment. Initially, interleukin-10 levels rose, type 1 regulatory T cells and tolerogenic monocytes and plasmacytoid dendritic cells were recruited, and T-cell proliferative responses to self-antigens decreased.

Radiotracer tracking showed that the modified red blood cells were distributed mainly in the liver and spleen. This is consistent with observations in mouse models and supports the role of the liver and spleen as microenvironments for inducing immune tolerance.

The researchers said that because the primary endpoints of the phase 1b trial were safety and tolerability, it was difficult to statistically assess clinical efficacy. However, they added that because detectable immunomodulatory signals appeared after a single dose, long-term clinical benefit must be confirmed in a large randomized controlled trial.

Autoimmune diseases affect more than 5% of the global population. The researchers said this platform technology, which uses a patient’s own cells as carriers of tolerance, could be extended beyond multiple sclerosis to more than 100 autoimmune diseases.