Immune cells that colonise the brain and damage neurons could be a new therapeutic target for MS
Scientists from the University of Oxford and the University of Hamburg have discovered that specific immune cells accumulate in the brains of multiple sclerosis patients over the course of the disease. Their results, which could form the basis for new therapeutics for multiple sclerosis, have now been published in the journal Med.
Multiple sclerosis (MS) is a disease in which immune cells attack the brain, often leading to severe disability. In the early phases of the condition, it is possible to suppress these immune cells with drugs. But as the disease progresses, the efficacy of this intervention declines, and more and more neurons die. The scientists set out to investigate the theory that this therapeutic resistance is caused by a gradual accumulation of immune cells in the brain. Shielded behind the blood-brain-barrier such colonising immune cells could damage neurons beyond the reach of current drugs.
‘Studying immune cells in the brains of patients was a real puzzle to solve – naturally, samples from the brains of living humans are not readily available’, says Dr Max Kaufmann, MD and scientist from the University of Hamburg, who carried out the bioinformatic data analysis. In the end, the team solved the problem by studying blood samples collected from patients treated with the drug natalizumab (Tysabri®). ‘Natalizumab prevents immune cells from entering the brain’, explains Dr Kaufmann. We figured that under these conditions immune cells normally homing to the brain would be trapped in the blood, where we could analyse them’.
Using high-resolution single-cell sequencing methods, the scientists were able to identify immune cells in the blood of natalizumab-treated patients and characterise them in detail. This analysis enabled them to pinpoint ways in which future therapies might inhibit or deplete these specific immune cells, before they can colonise the brain.
The team then followed these immune cells all the way from the blood to the brain. They analysed rare brain tissue samples from deceased late-stage MS patients using a cutting-edge called spatial transcriptomics. Using this technique, it is possible to measure thousands of RNA molecules in a piece of tissue while preserving spatial resolution. In this way, the researchers demonstrated that those specific immune cells were indeed localised in areas of brain damage in late-stage MS.
‘Our results suggest that the colonisation of the brain by immune cells could be an important factor in the therapeutic resistance of late-stage MS’, says Professor Lars Fugger, Director of the Oxford Centre for Neuroinflammation. ‘At the same time, we demonstrate that these cells can be mobilised to the blood at an early disease stage, raising the possibility that they could be reached by novel therapeutics.’
The study was released in Med accompanied by an editorial by Professor Lawrence Steinman from the University of Stanford, co-inventor of Natalizumab, where he stresses the importance of the findings and discusses new therapeutic strategies that could follow from them.