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After reading the exerpt from this study, it appears that Dr. Behan was right in his Pathogenesis of MS when he stated that the EAE model for MS research was not beneficial at all for human MS.

How many years has it taken them to come to this conclusion?

Harry

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Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L.
MRC Human Immunology Unit and Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.

The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.

Harry,

I believe the best models to study are the Quaking and Jimpy mouse strains that develop neurodegeneration, apparently due to an imbalance in their polyamine levels. (Russell DH, Meier H. Alterations in the accumulation patterns of polyamines in brains of myelin-deficient mice. J Neurobiol 1975;6:267-75.) This type of neurodegeneration could be similar to what Barnett & Prineas were seeing in lesions preceding any autoimmune inflammation. Polyamines can alter the blood-brain barrier, interfere with ion channels and signal transduction, and alter chromatin. Spermidine (one of the polyamines) is believed to be a constituent of myelin. I don't know if the Quaking and Jimpy mouse strains are even available anymore since 1975 is the last time I saw them mentioned.
A similar problem would seem to be occurring in lupus mouse models where the models do not seem to resemble the human disease once you get down to the subcellular level. For example, in lupus some patients have autoantibodies to Alu-RNA/protein complexes. Those same autoantibodies do not immunoprecipitate other RNA/protein complexes. This implies something unique and autoantigenic about the Alu-RNA/protein complexes. But mice do not have Alu sequences in their genomes although humans have ~500,000 copies of these short genes. So you are never going to be able to model this aspect of the disease in mice without great difficulty, and it may, in fact, be a critical aspect of understanding the disease. I believe it is an important point in understanding both MS and lupus. Alu sequences are rich in GC bases. If a reverse transcriptase were to reverse transcribe the Alu RNA to Alu DNA, the Alu DNA generated would require methylation or else it would be interpreted as foreign DNA and probably provoke an auto-immune reaction. You would never see this in mouse models.
The free DNA in serum of lupus patients is rich in GC and Alu sequences and would appear to be a significant indicator of what is going on. Of course, if you believe autoimmune diseases originate from malfunctions in the immune system, then you might not consider this important and go back to your mice to try more lymphokine and T cell experiments.
Just to restate my beliefs: I think autoimmune diseases usually originate in non-immune tissue cells, such as oligodendrocytes in MS or
chondrocytes in lupus, and not as often originate from immune system malfunctions. I think that MS and lupus have similar mechanisms but different consequences/symptoms based on the accessibility and cell type in which they occur. I think the tissue degeneration (neurodegeneration or connective tissue degeneration) are related to the auto-antigen generating event but they can occur separately. In effect, neurodegeneration can occur without inducing an auto-immune reaction initially or an auto-immune reaction can be provoked by the cells before they have begun to exhibit neurodegeneration.

Wesley

Wesley,

Your extremely well written post makes a lot of sense.

Of course, if you believe autoimmune diseases originate from malfunctions in the immune system, then you might not consider this important and go back to your mice to try more lymphokine and T cell experiments.

What did Einstein say one definition of stupidity was..." doing the same thing over and over again and hoping for a different result." I can't help but apply some of that rationale to how they have been trying to solve the MS mystery for so many decades by using that MS model. The mouse is "induced" with mouse MS and then the researchers try and figure out what is going on. It's no wonder that so little progress has been made with this disease!

Just to restate my beliefs: I think autoimmune diseases usually originate in non-immune tissue cells, such as oligodendrocytes in MS or
chondrocytes in lupus, and not as often originate from immune system malfunctions.

I share this theory with you and wished that more MS researchers had explored this avenue in the past. Perhaps had they done this, we would be much closer to figuring out MS.

Take care.

Harry

Great post Harry! Wesley your post is an interesting variance on the old theme which is new to me. Well done.
Here is another paper on this same subject. http://www.ncbi.nlm.nih.gov/entrez/quer ... med_docsum
I own the whole citation and it is a very in depth look at the cellular differences with charts and tables. EAE and MS are so utterly different that it is incredible that we get anything from EAE. In fact it says in that paper that only one medicine has ever gone from mouse model to people, and that one was copaxone (which does not work in people the way they thought it would at all). Every other medicine that helps EAE does not help people, or helps only a tiny bit.

In reality what EAE is is our THEORY about what causes MS forced into reality on mice, then us treating the THEORY as if it were the reality of MS
Insanity! In the paper I linked the conclusion is that essentially we need to look at PEOPLE with MS for what is actually there, not what we think is there.
One such look gave us Prineas and Barnetts paper. Another is the Lucchinetti work. We need more like that.
marie

Wesley,

I am curious since your point of view as a researcher if you have any great vibes about some of the therapies currently in clinical trials.

Also, the Myelin Repair Foundation has one of its researchers perfecting a mouse model for MS research. It has been too long since I read the article about it that I can't give any specific names or time frame.

I know that the self imposed time frame for this foundation finding a treatment for MS is less than 4 years now. Their reports, which seem to come out about twice a year, list some very promising results.


gwa

gwa,

I am in cancer research. I haven't studied the drugs being used in MS treatment in any detail. I'll try to educate myself on them. My interest in auto-immune diseases is to figure out the causes and develop my theories on the mechanisms. The genes that particularly interest me and relate to my theories are also involved in cancer. So I am trying to get a grant to study those genes in relation to cancer and finding cancer therapy drugs, which hopefully will also work for auto-immune diseases.

Wesley