Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4(+) T cells. Characterization of this model reveals both Th1 and Th17 CD4(+) T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in calibre. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly.
There is a need to study remyelination. Some models involve chemical demyelination but they repair quickly and there is no autoimmunity in the picture, so in this study they transfer in some myelin reactive T cells and remyelination was slowed You can read the rest.
Using chemicals to demyelinate animal models is currently the set tool to study remyelination. If these are youngish animals they will remyelinate in a few weeks without doing anything, but if you add remyelination drugs it works quickly. The problem with this model is that it lacks the gliosis characteristic of the MS lesions we would want to repair. In this new model it looks like larger axons are damaged. The question is does it add to the science or the laziness.
Whilst a new model is good, what about the old models? Maybe if they were used in a more informative way then they could give the answers.
So currently lets do the quick and dirty and give drug when the demyelination is occurring. We see that paralysis is blunted and so is every thing else downstream. Great but we already have anti-inflammatories that could do this.
Is it really remyelination or is it anti-inflammatory, as the demyelination never happened in the first place. So using this we can get a drug that never gets in the CNS and inhibits EAE and see natural repair and we can claim remyelination. However would it not be better to cause the damage, get rid of the damaging inflammation or let it subside and then see if our drug of interest causes real repair.
It sort of seems obvious but the problem is it may take a few weeks longer, the result may(well lets face it they probably will) be less impressive and it may not work and so there will be no publication.
However, should we not be asking what is the translational value of such experiments?
The logical experiment is not to start treating progressive MSers in the off chance that it may affect long-standing demyelination, but do this during relapses and try and show better functional recovery.
However, should we blame the basic scientists for doing this? Their goal is to find repair agents…or should we look at the neuros who see the work and translate it in a different way.
It may not be important, however history has shown us that failure to translate the experiments leads neuros to question the value of animal models, rather than look in the mirror.
This may seem rather negative, but I’m just keeping it real because I want better experiments/trials.
However, I also may be talking guff because people are beginning to “big-up” results coming from the clinic translating these models..Let’s hope this is the case.