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.
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.
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.
EAE in NOD
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.
“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.
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.