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Thursday, 11 October 2012

Education:Interpreting EAE

Because of the Failure of Immunosuppressive Drugs to Stop Progressive MS other ideas of what maybe happening in MS cam e to light. Progression is currently though to result from nerve damage.

Now, virtually every paper on EAE says that their drug exhibits neuroprotection (protects nerves from damage). This creates false hope to progressive MSers. Why because the EAEers are often over interpreting their data. They are also still of a mind set that MS is all about autoimmunity.

That nerve lost was a feature of MS was seemingly forgotten until 1998, when some pathologists brought it back to the attention of the World. So if you search the academic literature with the terms   "neuroprotection" and "EAE" before 1998 you get zero hits. Since 1998 it has been increasing year on year and now virtually every EAE paper claims neuroprotection. But do they every show it? I say not hitting yourself over the head with a hammer saves nerves. Of course this is obvious but EAEers fail to see this over and over again!!!!.
It should be obvious that if a damaging immune response never reaches the brain, it is clear that there will be no brain damage. Unfortunately most EAEers do not see this. They dip their heads in the sand and think that immunology is the cause and the solution of MS. However, progression in MS has yet to respond to immunosuppressive drugs. This should tell them that they need to remove the blinkers. This indicates that we have to think n a different way to save nerves in MS. So to find nerve protecting drugs we need to deal with the consequences of disease so... So the development of disease is a cascade if you do not have one event you will not get the next event so if you do not become sensitized then immune cells will not accumulate in the CNS (infiltration) this will not cause neurological disease and it will not cause nerve damage and this will not leave you with a neurological deficit.....simples. So if you do not get immune attack of the CNS, then there will be no clinical disease and you will not get nerve damage. However a different approach needs to be used for clinical treatment of progressive MS. The damage is occurring in MS. We need to deal with it so we have to target the consequence of disease, rather than always focusing on the cause. Therefore where the animal recovers to is important, especially when the drug has no effect on the severity of disease. Therefore the deficit after the attack is the important endpoint. So if you look at the neurological profile of an EAE study (below) and you see a delay in onset and//or a reduction in the severity of disease. The treatment is immunosuppressive!!!! This is invariably the case even if the author is claiming otherwise. Therefore you should expect to see less infiltrate and less immunological events, such as less cytokine produced. We have seen this time and time again and when you think the drug is an immunosuppressive that is OK, but when you think it is a repair drug you can be misled. For example early stem cell studies were attributed to repair, but subsequently (often years later) shown to be due to immunosuppression.  If use this guide for interpretation it was obvious from the start. If the drug does not eliminate the clinical disease and they show pictures, where their are no white blood cells etc in the CNS, they are selecting unrepresentative areas as you do not get disease without something happening in the CNS. These drugs are better candidates as neuroprotective agents for MS

As clinical disease resolves there is likewise a drop in the white blood cell activity in the CNS. This way you get recovery from neurological insult. However, if a drug is neuroprotective, without immunosuppressive activity, you do not see the drug stopping the disease from occurring or reaching its peak, but neuroprotective events are seen with a failure to accumulate of residual deficit.  This has been shown for a few drugs. We can go even further and  show using EAE that neurological progression can occur even if the drug is immunosuppressive, but the EAE model needs to be used differently from the way most people use it.

However, if you use this simple approach and view the clinical data before you read what the author is telling you to see, then you may be more sceptical about the claims. So "Cure of the Week" that occurs in EAE every week can be put into better perspective. It is possible to completely eliminate relapsing EAE is the drug showing a marked effect or just a marginal change in disease course.

Using this approach ask yourself are some of the drugs claimed to be neuroprotective, just plain old simple immunosuppressives agents or are are some of the repair agents actually being immunosuppressive and just allowing the natural recovery processes to act. Maybe I'm just being cynical.

Posted by MouseDoctor at 06:00 
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