This Is MS Multiple Sclerosis Community: Knowledge & Support

Hey, here's a new one. Unless someone has posted this prior to my joining this Board.

Anyone seen THIS article yet? It's dated 2004, so it's fairly new.

It basically explains all the DIFFERENCES between mice and humans and is specifically directed at immunology!

Oh, boy.....when I read this one, I thought, we ARE in trouble now! HAH!

Take a gander at this when you get a chance. (Note the main differences of MHC, caspases, AND the fact that mice do not exhibit the same ion channel functions as humans do! Uh.....correct me if I'm wrong, but aren't those things of PARTICULAR importance in any type of laboratory testing in MS? Oh, boy...........) There's more than that, but I couldn't stand reading any more of such "good news".

I don't even want to think about the implications.

Deb

I quote from the publication. (The full article can be found at http://darwin.bio.uci.edu/~cchughes/Pdf ... %20men.pdf

"....Both human and mouse EC express MHC class I. Most human EC in vivo also constitutively express MHC class II molecules, whereas mouse EC do not (80). Thus, human EC can present Ag to CD4+ T cells, as well as to CD8+ T cells. A major costimulatory molecule on human EC is CD58 (LFA-3), a ligand for CD2 (81). Mice do not have the gene for CD58, which arose by CD2 gene duplication after the two lineages split. In mice the CD2 ligand is CD48; however, the distribution of this molecule differs from that of CD58 in humans, and the two-dimensional affinity for the mouse CD2-CD48 interaction is 40- to 50-fold lower than that for human CD2-CD58 interactions (82). In addition, gene deletion and Ab blocking studies have shown that mouse T cell activation is much less dependent on CD2 interactions than is the case for human T cells. Human EC also express CD40 and the ICOS ligand GL-50, whereas murine EC do not (83, 84). ....

....A critical step in activation of a T cell is the generation of a sustained calcium flux. In human T cells the inward flow of calcium ions is balance by an outward flow of K+, mediated in large part by the Kv1.3 K+ channel. Inhibitors of this channel very specifically block T cell activation in vitro and are being pursued as novel immunosuppressive agents (64). However, in vivo evidence to support such a function is missing as mouse T cells do not express this channel (65)....."

EDIT: Ok, to be fair, they do end the article with this summary, which I have to admit is very true.

"....Summary
While it is hard to draw global conclusions about the significance of differences between mouse and human immunology, it is worth considering the possibility that any given response in a mouse may not occur in precisely the same way in humans. While caution in interpreting preclinical data obtained in mice is clearly warranted, we believe that with these caveats in mind, mice will continue to be the premiere in vivo model for human immunology and will be absolutely essential for continued progress in our understanding of immune system function in health and disease."

Deb,

Is it not surprising then, there has never been a MS treatment which has been effective in a mouse that has ever worked in a human!!

That's why I never get excited when researchers announce some new discovery in that poor MS mouse....because it is pretty much guaranteed that it won't work in a human.

Harry

Hi, Harry!

I see you had the same reaction as I did. The second thing I am really sort of surprised about is that it was actually published so widely.

Looking at it positively, it's a good thing for researchers to know and take into consideration. Looking at it otherwise, how can we even be assured that ENOUGH researchers know this and are factoring this in?

I've always been cautious about "new" discoveries, also. But that was mainly because I've just learned to be that way as a general rule. Now I have some confirmation that my caution may be justified. I'm not sure if I'm happy about that or not, ya know?


Deb

How can we get this info into the hands (minds) of the researchers!? I hope Art has a chance to read this study.

Bill F,

Most if not all researchers are very aware of this information. Don't forget who hires the researchers....most of the time it is the drug companies who are trying to develop new products for one reason and one reason only...to make lots of money!

Now there is nothing wrong when running a business in trying to make lots of money but in the business world of health and drugs, it is slightly different.....you are dealing with people's lives! Unfortunately this takes a lower priority than the monetary incentive. How else can we explain using that poor MS mouse to research MS and make comments that the CRAB drugs are the best route to go?!! Now they are combining these drugs in the hope that mixing and more of them is better in treating your MS!

Harry

Geez, Harry...........another Catch 22. Well, I'm going to believe as you do, that most of the researchers DO know about this, but with one "small" twist. I think I'll add that the majority of them MUST be factoring this in with their research. BUT......then again.......How effectively can you factor in something that doesn't even exist in a mouse model?

(Hey, I'm not jumping back and forth over the fence, am I? LOL) Ok, let's leave it at "I don't have enough factual information at hand with which to make an informed opinion or draw a conclusion." That's my legal eagle side coming to the fore!

Yea, maybe Art will weigh in. He's chatted with most of the pharmas recently.

Deb

Deb,

I don't think you should be concerned that you don't have all the "proof" required when it comes to talking about the "poor MS mouse". Two years ago Dr. P. Behan stated that the EAE mouse was all but useless when it came to extrapolating therapies that worked on the mouse but certainly were abysmal when it came to applying them to humans. Like he said, there hasn't been one treatment that was successful on the mouse that translated to human benefit.

He did say the EAE model was great for following the disease in a mouse but that's where it stopped.

Harry

From what I have read, the mouse is their choice as it is easy for the scientists to genetically alter the mouse to make it have symptoms "similar" to the specific disease being studied.

Also stated was mice breed robustly,they make a great cost effective test subject as they reproduce as fast as they are altered.

hmm? If they know which genes and how to alter these specific genes to create a "similar" disease , maybe they should focus on the genes they alter???

Yes, I ALMOST made a comment about the EAE model of mouse MS with my last post, but I stopped myself.

Remember, I did express on another thread the "confusion" I had regarding Dr. Sriram perhaps still using the EAE model of MS at Vanderbilt. But of course, I don't know for certain that Vandy is still only using the EAE model nor am I aware of which EAE model they use (PLP or MOG). I only got that off of their website. I hope that they use more than one model of MS, though, and their website just hasn't been updated in a while.

I'm not certain how equivalent the Theiler's murine encephalomyelitis virus (TMEV) mouse model of MS is to humans, either. This one has been used quite often.

Then there's MOG induced EAE, but again, this model is slightly different than the other two I just mentioned (PLP and TMEV). This one might be the best one so far, though. Although, who can say for sure?

Oh, man...........not only do patients have to be knowledgeable and cautious about new claims on research findings, they need to be aware of the specific mouse "model" of MS that the findings were based on!

Too many generalities, not enough specifics.



Deb

That's where Dr. David Hafler comes in, Philip.

NOW you get into the money factor. As Art mentioned in another thread, it costs MILLIONS to try to do genetic research.

Catch 22.

Deb