Modelling Progressive MS

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We have been wanting to model progressive MS so that we can find drugs to treat it. The communty view was that there were no animal models of progressive MS, but we said yes there is! You can induce relapsing disease to get a secondary progressive phenotype, where the drugs that stop relapses do not halt progression.

Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis.Pryce G, O’Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D.J Neuroimmunol. 2005;165(1-2):41-52. 

However, time and time again people got up at meetings and said there are no model of progressive disease, even 5 minutes after I had spoken.

You create something but it is only when other people do it that people start to believe it.

Modeling compartmentalized chronic immune-mediated demyelinating CNS disease in the Biozzi ABH mouse.Nishri Y, Fainstein N, Goldfarb S, Hampton D, Macrini C, Meinl E, Chandran S, Ben-Hur T.J Neuroimmunol. 2021 Apr 21;356:577582. doi: 10.1016/j.jneuroim.2021.577582. We explored whether experimental autoimmune encephalomyelitis (EAE) in Biozzi mice recapitulates temporal dynamics of tissue injury, immune-pathogenesis and CNS compartmentalization occurring in progressive multiple sclerosis (MS). Chronic EAE exhibited relapsing and progressing disease, partial closure of BBB, reduced tissue inflammatory activity, and development of meningeal ectopic lymphoid tissue, directly opposing (potentially driving) spinal subpial demyelinated plaques. A T cell predominant disease during relapses transformed into a B cell predominant disease in late chronic EAE, with high serum anti-MOG reactivity. Thus, late chronic Biozzi EAE recapitulates essential features of progressive MS, and is suitable for developing disease modifying and regenerative therapies.

However, the problem with using this model to study progressive disease, is that it takes a lot of time to do the experiments properly, and as you have to check the beasties every day for months, no weekends off, no breaks and when it doesn’t work and it can be soul-destroying. I remember in the early days when it was only me, I did not have one day off in the whole 2 years except Christmas day (when animal lab technicians gave me a day off),……I thought I was working in a US lab:-) . However it is harder and harder to do such research in the UK. If an animal dies then the Home office (Government Inspector) has to be informed and some of them hold an inquest into what happened. Progressive EAE is very unpleasant because just like humans, the beasties develop additional signs and symptoms.

However, a number of years ago we began to focus on B cells and I have to say that once we showed that early B cell treatment did very little in the model and humanised mice, which were mice filled with human cells, were not good enough as a replacement, therefore we largely gave up using mice for such mechanistic studies. We simply focused on using them to help the drug development process. Sadly there was no process in 2020 in London. COVID-19 has taken its toll. However, we continue to watch others put square pegs in round holes in relation to understanding B cell immunotherapy and it rather re-inforces our view that we were right to do what we did..

I wish the Israeli/Scottish group all the luck in finding useful treatments for progressive MS.There are other systems to use, but I would have to repeat them to believe them. However, I have said it many times, if the clinical trial design cannot find useful agents, it will not matter what the animal studies suggest.:-(

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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5 comments

    • It depends the first iteration of these do not develop B cells properly therefore they are lacking. It has also proved difficult although not impossible to get EAE in these. I think a group in Australia was furthest along but they were not getting enough support…animal experiments are very expensive. I believe a group in germany got them infected with EBV…interesting. It would take a big effort as I think you have to give the mice extra human genese to make this effective so alot of crossing and cash…and time

  • So MS progression is due, in part, to a transition of a predominantly T-cell driven relapsing remitting phenotype to a B-cell driven progressive phenotype. B cells take up residence via lymphoid tissue in the meningeal space with production of anti-myelin antibodies to various antigens e.g. anti-mog. The reason it is so difficult to treat is finding therapies that penetrate the CNS and target these myelin specific B-cells in the hard to reach meninges. Is this correct?

  • Reading about your experience with animal trials reassures me that the movie 28 days later is not an accurate depiction of a typical animal lab in the UK. But why do people have to be soo dramatic and storm off meetings/lectures. What’s the worst thing that could happen? you learn that something doesn’t work?

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