Why mouse models of stroke and MS don't work
April 22, 2012 at 8:51am
MS is not the only neurological disorder which has a flawed rodent model. Turns out, stroke researchers just aren't happy with their mouse model, either. Why? Because the immune response after stroke is different in mice and people.
EAE is not MS in humans.
Believe it or not, the current MS drugs cure mice of EAE. But they sure do not cure people of MS.
What's the problem? There are many problems with the EAE model.
Here's my favorite description of what's wrong with EAE, from Dr. Michael Dake--
"There's an animal model, but it's not really, unfortunately, like most animal models, it's not really a human model. Basically, you take like a mish of ground up spinal cord and brain from some other species, you mix it with some oily substance, some TB bacilli, and some bordatella pertussis, some whooping cough toxin, and inject it into peridium, and what you get is this whopping inflammatory response, and that's good because you get the accelerated disease process, but obviously in humans, it's a much more chronic and progressive thing."
People with MS haven't had this cocktail of viruses injected into their brains. (Good thing!)
But there's much more. The immune system of rodents and humans are very different, too.
Stroke researchers understand that their rodent models are not working.
This is because the immune reaction after ischemia is very different in rodents when compared to humans.
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Here is a recent paper on the problem with the rodent model of stroke--and the difference in the immune response in mice and men.
Important to note---the immune system responds after stroke, just as it does in MS. Ischemic injury, or lack of oxygen to brain tissue, calls in the immune system to clean up dead cells. This happens in all mammals.
The rodent immune cell composition is remarkably different from that of humans.
Specifically, rodents have a lymphocyte predominance with a 1:5 ratio of neutrophils to lymphocytes.
Humans have a 2:1 ratio of neutrophils to lymphocytes.
What does this mean? Time for some explaining.
Neutrophils and lymphocytes are both types of white blood cells that make up the innate immune system of all mammals.
Neutrophils are the most abundant type of white blood cells in humans. They are formed in our bone marrow. They migrate thru blood vessels and get to the site of injury the most quickly. They are filled with microscopic granules, little sacs containing enzymes that digest microorganisms. Think of them as the first responders. They are white and are the predominant cells in pus. (gross, I know...) Humans have two times more neutrophils than lymphocytes.
Lymphocytes are the white blood cells formed in the lymph tissue. They are clearish/blue (see pic) Lymphocytes are broken into categories of T and B cells and NK, or natural killer, cells.
Lymphocytes are what MS specialists claim is behind the autoimmune attack in the MS disease process.
But mice have less FIVE TIMES MORE lymphocytes then neutrophils.
Immune system in humans= NN / L
Immune system in mice = NN / LLLLLLLLLL
Can you see how this might affect the immune reaction to stroke and MS in mouse models???
--Perhaps this is why the tragic flaw of PML in lymphocyte sequestering drugs like Tysabri wasn't discovered until they were administered to humans. The mice never developed PML.
--Perhaps this is why the tragic flaw of PML in lymphocyte sequestering drugs like Tysabri wasn't discovered until they were administered to humans. The mice never developed PML.
The differences go much further and deeper---for those who enjoy reading research papers, here is a tidbit from one I'll link below of the differences in mice in men, as related to MS research and how the difference in neutrophils and lymphocytes changes the immune reaction ---
Experimental autoimmune (allergic) encephalomyelitis is a widely used model for MS that mimics the demyelination seen in central and peripheral nerves in MS. Several studies have indicated that IFN-γ is protective in experimental autoimmune (allergic) encephalomyelitis as neutralizing Abs exacerbate disease, potentially by blocking induction/activation of suppressor activity (69, 70). It was surprising, therefore that clinical trials were not successful; indeed they were stopped because treatment with IFN-γ was found to exacerbate disease
An interesting difference exists in the appearance of delayed-type hypersensitivity (DTH) reactions in mice and humans. In humans, around four hours after Ag challenge neutrophils can be seen forming a "cuff" around the venules. This is followed by a dramatic influx of mononuclear cells, such that by 24–48 h the lesion is mostly mononuclear with a mix of T cells and macrophages (73). Paradoxically, in mice where the peripheral blood has a relative paucity of neutrophils compared with humans, the DTH response tends to be more neutrophil rich (74). In addition, elicitation of murine DTH requires much higher concentrations of Ag than in humans.
All MS drugs are being created for and tested on mice with EAE.
EAE is not MS, it never was, it never will be.
The immune system is activated in ischemia.
Time to bring the stroke, TIA and MS researchers together.
Time to look at cerebral perfusion in human beings.
Time to look at cerebral perfusion in human beings.
Time is of the essence.
Joan
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