Mice and Relapsing Progressive disease

Ignatius Arokia Doss PM, Roy AP, Wang A, Anderson AC, Rangachari M.The Non-Obese Diabetic Mouse Strain as a Model to Study CD8(+) T Cell Function in Relapsing and Progressive Multiple Sclerosis. Front Immunol. 2015;6:541. doi: 10.3389/fimmu.2015.00541.

Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on central nervous system (CNS) myelin. Although CD4(+) T cell function in MS pathology has been extensively studied, there is also strong evidence that CD8(+) T lymphocytes play a key role. Intriguingly, CD8(+) T cells accumulate in great numbers in the CNS in progressive MS, a form of the disease that is refractory to current disease-modifying therapies that target the CD4(+) T cell response. Here, we discuss the function of CD8(+) T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In particular, we describe EAE in non-obese diabetic (NOD) background mice, which develop a pattern of disease characterized by multiple attacks and remissions followed by a progressively worsening phase. This is highly reminiscent of the pattern of disease observed in nearly half of MS patients. Particular attention is paid to a newly described transgenic mouse strain (1C6) on the NOD background whose CD4(+) and CD8(+) T cells are directed against the encephalitogenic peptide MOG[35-55]. Use of this model will give us a more complete picture of the role(s) played by distinct T cell subsets in CNS autoimmunity.

EAE started as a CD4 T cell mediated disease and is morphing into a CD8 mediated disease to accommodate the view that more CD8 T cells are found in MS and it will morph into being a CD20 B cell disease to accommodate the view that CD20 B cell depletion controls MS. 

However dealing with relapsing MS has become less of a priority as focus has been shifted towards progressive MS. We have developed a secondary progressive model which follows a relapsing remitting or to be more precise a relapsing progressive disease such that there is increasing poor recovery from attack after each relapse and then the relapses burn out and slow neurological worsening occurs that does not respond to T cell therapy. This happens in ABH mice and others if you observe them for long enough

AP= Acute first phase paralysis, RL = relapse RL1= first relapse, RL=2 = second relapse RM1= first remission 

This takes along time so we interested that the NOD mouse MOG peptide model has been described as a progressive Model above and elsewhere

Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, Monsonego A, Bar-Shir A, Engel Y, Gozin M, Weiner HL. J Clin Invest. 2008; 118(4):1532-43. 

Look at the line and you say there is progression and so its a secondary progressive model however it responds well to T cell therapy, just like our relapsing model. 

However we have been asking that people include more information about their line graphs…..Baker D, Amor S. Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2012 ;242(1-2):78-83……so they can be interpreted. 

We know that not all of our ABH experiments look as pretty as that above and sometimes we get.

Top one looks like there is a strong attack compared to the weak one in the NOD,it is after all a low EAE susceptible strain.

Baker D, Rosenwasser OA, O’Neill JK, Turk JL. Genetic analysis of experimental allergic encephalomyelitis in mice. J Immunol. 1995;155:4046-51. Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that exhibits many pathologic similarities with multiple sclerosis. While products of the MHC are known to control the development of EAE, it is clear that non-MHC products also influence susceptibility. The chromosomal locations of these were investigated in selective crosses between MHC class II-compatible, EAE-susceptible Biozzi ABH, and low responder nonobese diabetic (NOD) mice. The disease was dominant and highly influenced by gender in the backcross one (BC1) generation. Female mice were significantly more susceptible than male mice. Segregation of disease frequency of female animals in this cross suggested that EAE was controlled by a major locus. Although microsatellite-based exclusion mapping indicated that a number of regions on chromosomes 5, 6, 7, 8, 9, 10, 11, 12, 13, and 18 showed evidence of linkage (p < 0.05) compared with expected random distributions of alleles, disease susceptibility was most strongly linked (p < 0.001) to chromosome 7. However, by selectively analyzing animals that were either severely affected or almost normal, additional susceptibility loci were mapped on chromosomes 18 and 11 that were linked (p < 0.001) to resistance and the development of severe disease, respectively. The data indicate a major locus on chromosome 7, affecting initiation and severity of EAE that is probably modified by several other unlinked loci. These localizations may provide candidate loci for the analysis of human autoimmune-demyelinating disease. (So MS is like EAE and polygenic and it was clear at that point that the technology was no good enough to find the actual genes (as was the case in humans too) and so stopped hunting…Now I have the whole genome sequence of ABH (and NOD mice) and could go back and look at this).

However doesn’t it look like after the first attack there is progressive worsening. However, this is simply the effect of an asynchronous, relapsing-remitting disease that showed increasing poor recovery. The poorer the recovery correlated with more attacks. So you don’t want to tolerate attacks (relapses) and should aim to not have them. It is plain to see in animals humans will be no different.  

In the case above at the individual level disease is relapsing remitting with increasingly poor recovery, not truly progressive as appears from the line graph.
So back to the NOD Model. I have emailed a lot of people doing NOD EAE and they say it is a relapsing model. So let’s look at what what is published by some authors of the 2008 paper as they show responses of individual mice. 

Levy H, Assaf Y, Frenkel D.Characterization of brain lesions in a mouse model of progressive multiple sclerosis. Exp Neurol. 2010, 226:148-58

This is clearly also an asychronous relapsing disease with variable amounts of recovery and is therefore not a true progressive disease in its early stages, when it is modified by T cell therapy.  However there may be true post-relapse secondary progression just as occurs in the ABH mouse model as they say.


Levy H, Assaf Y, Frenkel D.Characterization of brain lesions in a mouse model of progressive multiple sclerosis. Exp Neurol. 2010, 226:148-58. We show that immunization of non-obese diabetic (NOD) mice with myelin oligodendrocyte glycoprotein peptide 35-55 leads to the development of relapsing-remitting stages, evident from days 20 to 70, which then develops into a chronic progressive stage. This cycle is similar to MS stages found in humans. Brain MRI gadolinium-enhanced T1-weighted image analysis showed an increased blood-brain barrier permeability in brain gray and white matter specific to the corpus callosum, fimbria, and internal capsule as found in humans. MRI fractional anisotropy analysis showed demyelination and axonal damage in identical regions. We suggest using NOD mice as a suitable model for studying MS using MRI methods toward future diagnostic and drug development.

This view is indeed supported by other studies that the disease is relapsing in NOD mice is relapsing without synchronicity.

Levy Barazany H, Barazany D, Puckett L, Blanga-Kanfi S, Borenstein-Auerbach N, Yang K, Peron JP, Weiner HL, Frenkel D.Brain MRI of nasal MOG therapeutic effect in relapsing-progressive EAE.Exp Neurol. 2014 May;255:63-70

“As each mouse has a relapse and remission at different time points, we calculated the average clinical score of each relapse and remission for each individual mouse . We found that the average clinical score during relapses (1.7, 1.8, 1.9, 2.3, 2.5)….whereas remission in control animals (0.9, 1.2, 1.7, 1.9).

C57BL/6 mice can go secondary progressive after one attack as can some ABH (although this is unusual) but it normally takes 3-4 attacks for this to happen and it it occurs quicker in males than females. However the progression is very slow and so you need to have ways to measure it the mouse EDSS is too insensitive.

In the animals it looks like a “slow burn” occurs around lesions this may occur in humans too. It is also possible humans that some progression progression could still be due to relapses, which may be largely subclinical relapses. We know that about 85% of lesions go un-noticed clinically but each lesion will be causing small amounts of damage and over time this may cause accumulated damage.

However, I predict the NOD (Non-obese diabetic-this spontaneously develops insulin dependent diabetes) mouse will become more and more important because they have made NOD mice that lack T and B cells called a NOD Scid (Severe combined immunodeficiency) mouse that lacks T and B cells (So it can’t reject anything). They also make it even more immunodeficient by knocking out a few for immune genes and these are called NOG mice. 

Now you can transplant CD34+ blood stem cells and they repopulate the NOG mouse with human immune cells. These can then be studied to monitor human immune function. 

Once they are developed to have a fully functional immune system, we will be throwing the standard mouse models away because why work with mouse cells when you can work on human cells and you can test your drugs on them as some drugs e.g. cladribine does not work on mouse lymphocytes but only human and non-human primate cells. 

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  • Apologies – i NODded off when i read about the EAE SHI[t] mouse. What a load of bunkum. The researchers who publish this trash should be locked up. I'd vote to bring back public hanging. We now have highly effective therapies to halt inflammation and relapses. The challenge now is neuroprotection – preventing the remaining nerves, which are having to work overtime from degenerating / dying off e.g,g from being flooded with sodium etc. image Team G is the CNS – something whipes out Prof G, Dr G, Welsh Mouse. That leaves Heavy Metal mouse doing all the work. It's too much for him and the overload kills him off. He needed protection. Please no more MOG, NOGO, LINGO, DINGO…EAE. EAE is dead.

    • You may ask why I allowed this comment to surface, maybe I shouldn't. I see ProfG was talking about the blinkered Neurologists who won't prescribe a drug just because it has been used in cancer. Alternatively you can look at the data with an open mind.

      Likewise you can be blinkered about animal studies too. Many neurologists are so why not pwMS. Although EAEers seldom say Neuros are wasters, it does occur the other way round and likewise there are people like you who are of this view. No matter what I say or do won't change your potty mouth.

      You can take the view that animal studies are a waste of time and that we should not do any but then you wouldn't have any therapies to halt inflammation, because you wouldn't have the knowledge to make the technology or the willingness to risk $100,000,000 on a punt. So whilst you are berating MD & MD2 just think where the ideas come from and where does the data to support those human studies come from.

      So I have been talking to ProfG about a neuroprtective drug that could be used in MS tomorrow, it has patent protection, targets a biology that is consistent with saving nerves yet the company do not want to do the MS trial until they have animal data, so go figure.

      You can't have it both ways my friend and if you don't want to read anything new about EAE and experiments you don't have to do it, do you. But maybe if you did you would learn how to interpret the studies and work out if they are hope or false hope or even Bob Hope:-)

    • There won't be any further progress on neuroprotective agents without EAE. Baby, bathwater etc and sometimes even though a piece of research appears obscure/irrelevant, the passage of time reveals that that is anything but the case.
      The cannabis, simvastatin, phenytoin, lamotrigine, oxcarbazepine trials for neuroprotection in MS all had their foundations from (mostly our) EAE studies. No-one is going to take a punt on a compound being neuroprotective in MS without robust experimental animal data.

    • Will any of five drugs mentioned above ever make it to market ie benefit MSers? The early trials show promise and the process grinds to a halt.

    • Cannabis is already in the market……for some that is on the street corner but sativex is there. As for the others simvastatin phenytoin lamotrine and oxcarbazepine could i think be prescribed off label if we believe the minister

  • "Once they are developed to have a fully functional immune system, we will be throwing the standard mouse models away because why work with mouse cells when you can work on human cells and you can test your drugs on them as some drugs e.g. cladribine does not work on mouse lymphocytes but only human and non-human primate cells."

    How long until these super-meeses are developed? Any way of knowing?

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