El Behi M, Sanson C, Bachelin C, Guillot-Noël L, Fransson J, Stankoff B, Maillart E, Sarrazin N, Guillemot V, Abdi H, Cournu-Rebeix I, Fontaine B, Zujovic V.
Brain. 2017. doi: 10.1093/brain/awx008. [Epub ahead of print]
One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells.
Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes.
Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients.
Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination.
Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.
Last week we had the story that Treg cells produced a molecule that promoted remyelination and this week we have something similar but they take human cells and inject them into a nude mouse.
A nude mouse is a mutant mouse that does not make hair, but they also do not make T cells and so they can't reject human cells that are transplanted into the mouse. They injected a toxin to make demyelinated lesion as the toxin kills oligodendrocytes.