New EAE Model


For the rodent readers, this is one for you. So those who can’t give a stuff about our furry friends, this is not the post for you.

We are always on the look-out for models of MS. In this study they look at the myelin oligodendrocyte glycoprotein T cell receptor transgenic mice where all of its T cells react to this myelin protein. This can get EAE, but generatlly they get apparently sub-clinical neurological disease and get optic neuritis. This study says they have found another variant the limb clasper. I think I have to say that this is not a new variant, but they are simply looking abit more closely.

This sign is not new to me and I have seen it loads of times in EAE, however it is even more common in EAN. This is a disease of the peripheral nervous system. So as soon as I saw clasped hindlimbs I thought peripheral nerve problem. Indeed many years ago I saw it in a myelin basis protein T cell receptor transgenic mouse and suggested they do abit of histology in the peripheral nervous system and sure enough, that’s what they found .

Disease-related epitope spread in a humanized T cell receptor transgenic model of multiple sclerosis.

Ellmerich S, Takacs K, Mycko M, Waldner H, Wahid F, Boyton RJ, Smith PA, Amor S, Baker D, Hafler DA, Kuchroo VK, Altmann DM. Eur J Immunol. 2004;34(7):1839-48. We have generated such a transgenic line, called line 8, that co-expresses a high level of HLA-DR15 and a human TCR specific for HLA-DR15/MBP 85-99. T cells from the transgenic line are skewed to the CD4 single-positive compartment and produce IFN-gamma in response to peptide from mylein basic protein. Mice develop a spontaneous disease phenotype, showing poverty of movement, although this rarely develops into paralysis except following immunization with peptide.

So in this study of clasping mice they find problems in posterior spinal cord and spinal nerve roots. The nerve roots are the peripheral nervous system, So my hunch seems to be right. In this study the mice were left to age and problems go much worse. The problem is the the clasping comes and goes and yep that is just what I have seen. However this issue means it is difficult to score and therefore can’t really be used for drug screening. Also making experiments last over months, means that you can do fewer experiments. Will this model have utility?, I don’t know, but the problem is how to you validate it as a model, yep there is nerve and synapse loss in grey and white matter and you get ongoing axon injury but was is so new about this? We showed you can do this over twenty years ago in the standard model and people are not routinely using these models as they are too much hard work. There are no positive controls on which you can say this works in my EAE model and this works n progressive MS. Once you get the answer to the latter you probably don’t need the former.

Aged hind-limb clasping experimental autoimmune encephalomyelitis models aspects of the neurodegenerative process seen in multiple sclerosis. Cahill LS, Zhang MA, Ramaglia V, Whetstone H, Sabbagh MP, Yi TJ, Woo L, Przybycien TS, Moshkova M, Zhao FL, Rojas OL, Gomes J, Kuerten S, Gommerman JL, Sled JG, Dunn SE. Proc Natl Acad Sci U S A. 2019 Oct 22. pii: 201915141. 

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.

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    • Yep, if we purchase mice we would always buy females as males will fight and have to be housed singly, however our in house animals are weaned and group housed and the males don’t fight so we use both males and females.

    • We dont because we dont have one, when we were at queen square they got one just after we left. They look like the regular scanner but are smaller, and you have to put the mice to sleep so they dont move. When I was at my old job they had a 9T mouse scanner. In walked a workman with a hammer….hammer flying through the air….in to the scanner (a giant sized magnet)…£10 grand of damage//Oops

      • Talk about bad day at the office. Thanks for the insight. I was hoping it might be like that but google image search was slightly patchy, my other mental image was that you’d put 100s of mice on a little stretcher and do them all at once in the human one 🙂

      • My brother did his medical training in Montreal, Canada and it was back in the starting days of MRIs, so apparently no one knew not to put a metal desk in the room next to it. They started it up, and the desk flew against the wall, and stuck there. It was too expensive t shut it off and turn it on again, so the desk stayed attached, partway up the wall, for several years!
        Wouldn’t a veterinarian college have an MRI machine for animals? Just asking, should you need one, though, alas for the poor mice, cost is cheaper to autopsy them…

        • It is not the the issue, to move a sick mouse is a real problem with the home office, but to move animals to a place withthe scanner and this creates a problem monitoiring them. Also you cant move aniamsl back and forwards as it creates risk of speading infections,Next the issue is the anesthetic needs for an MRI, sick mice do not anesthetise well

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