Wednesday, November 30, 2005

Research: Is EAE a good model for MS?

MS research often involves experiments with animals that have been induced with experimental allergic encephalomyelitis. Like MS, EAE is a demyelinating disease, and can be induced in rats, mice, guinea pigs, rabbits, and monkeys. Studies involving EAE led to the development of Novantrone and Copaxone. But what if EAE wasn't as good a model for MS as we thought?
Despite many years of intensive research, multiple sclerosis (MS) defies understanding and treatment remains suboptimal. The prevailing hypothesis is that MS is immune mediated and that experimental allergic encephalomyelitis (EAE) is a suitable model to elucidate pathogenesis and devise therapy. This review examines critically the validity that EAE is an adequate and useful animal model of MS and finds credible evidence lacking. EAE represents more a model of acute central nervous system inflammation than the counterpart of MS. We propose to reconsider the utilization of EAE, especially when this model is used to define therapy. This will also force us to examine MS without the restraints imposed by EAE, as to what it is, rather than what it looks like. Ann Neurol 2005;58:939-945.

Link to abstract.
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Beth said...

I just read the review. It is very good and raises important points.

EAE is a Th1-mediated response, and can be induced by giving IL-2 or interon gamma. Although one paper suggested that giving human patients interferon gamma induced MS, this review points out problems with that study (a different review I just read summarizes that paper as most do). EAE involves CD4 T cells, while MS involves CD8- I'm not an immunologist, but I gather that is a big difference.

Even the idea of MS being autoimmune was questioned in the review that cited several papers where they found new plaques without any immune cell infiltration and that the death of the oligodendrocytes occurs first, and the immune cells are just there later to clean up the mess.

MS is not just a white matter disease, but infiltrates into grey matter. EAE is exclusively in white matter. The lesions in the grey matter fail to have any immune cells- ever- again suggesting the immune cell infiltration is secondary.

A myriad of chemicals have been shown to treat EAE (the paper has a table with everything but the kitchen sink listed), but fail miserably when tested on patients with MS. Wasn't that tryptophan thing on the EAE model- yeah- that probably won't do anything in humans either.

The authors of this paper are very good readers and do not pick up the commonly used lines to summarize papers in other reviews.

Why is the model still around when it clearly is not a model? This is the problem with NIH funding. The tend to fund labs that have published many papers in a model. The NIH does not like to fund high risk projects (although there is a specific section for higher risk projects). It is less risky for a researcher to write another grant on a sketchy, but established model than to write a grant on developing a new model.

Let me know if you don't want me hoarding comment space.

Doug Lee-Knowles said...

Thanks for the summary, Beth. I almost never get to read the studies, just scan the abstracts and scratch my head a bit.

Are there other models being studied or developed?

Beth said...

Yeah, it looks like there are a few labs developing new models- I just read the abstracts not the papers yet. There is scads out there on the EAE. The thing about science is that if you publish a lot about something it gets accepted as truth even if it is bogus and ends up in text books. Then it is difficult to publish something that goes against the current dogma. Frustrating as both the person trying to get these papers submitted, and a person who could benefit from good research.

The sad thing is how there are reports about treatments that cure EAE, get people's hopes up, and then it does nothing for MS.