MS lymphocytes making new myelin

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.

They then inject human cells, which they have activated,into the mice and find that they promote repair. As the mice were not genetically engineered e.g. to be MHC compatible, the T cells would not be able to talk to the lymphocytes. They go a test bleed from the eye by putting a needle into the retro-orbital sinus, which was banned (as their are alternatives) in the UK about 25 years ago, to check the cells are still present. They find there is variability in the repair potential, They found that MS blood cells demonstrate that multiple sclerosis lymphocytes did not interfere with OPC recruitment, but impeded OPC differentiation. This had an effect of via microglial cells and when they looked at 72 secreted molecule they found differences in three IL-7 and IL-20 which are immune growth factors and CCL-19 which is a protein that attracts cells called a chemokine. The latter was lower from people with MS. 
Taking advantage of our innovative in vivo model to study the role of human lymphocytes in remyelination, we demonstrated a strong implication of adaptive immune cells in this repair process. In particular, multiple sclerosis patient lymphocytes induce detrimental environment for the repair process notably by directing MIGs toward a pro-inflammatory M1 phenotype. Strikingly, the molecular cues needed for a successful remyelination were different when considering multiple sclerosis patient and healthy donor lymphocytes

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  • I think bleeding animals from the eyes is a disgusting practice, which is immoral and unethical especially as there are alternatives. British journals should not publish papers that use this practice if it has been banned in the UK for many years. The RSPCA may want to contact Brain to inquire why they published El Behi's paper. Have they heard of the 3Rs, which is supposed to be part of EU rules?

  • I guess it shows differences in regulations.
    It seems that in some places they think it is OK (search retroorbital bleed to get some gross pictures).

    e.g. This US website. (this was written in 2010)

    If we look on the NC3Rs website,
    it suggests it could be a terminal procedure to get alot of blood.

    I dont't buy this as you could easily get this from the heart after death.

    However, I have seen this done more than 30 years ago without anesthetic and it was certainly very quick in the hands of an expert.

    Anesthetic was not reported here, so did the current study use anaesthetic?
    Work on animals is covered by Directive 2010/63/EU, which is supposed to have the 3Rs as its core.

    Therefore one would hold that a case was made for this practise to occur as there are indeed alternatives if you want to do abit of flow cytometry.

    Maybe DrDoox can comment.

  • P.S. I have look again at the US website and this is about injection not a bleed but I think eye injections was stopped in UK. Too. Intravenous injection into small animals is an art and takes skill. MD2 is dead-eye dick as fare as i.v. goes. This is why the intrapertitoneal route is typically used.

  • Very cruel. And I bet the research ultimately contributes diddly-squat to real solutions for people with MS, anything to address the real problem of progression.

  • Got the impression that remylination was limited…and most
    recovery was simply due to brain reserve.

  • This is spinal cord remyelination, not brain. And you have the wrong impression, remyelination is COMPLETE after 3 weeks when HD lymphocytes are grafted. Look at the electron microscopy pictures. And science is not 'impression', it's objective interpretation of results

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