Could the new animal “Cure of the week” be the Cure

You want to hear about studies on cures. As a Jaded old Mouse I have been there before and we get “cure of the week” every week in MouseLand. But nothing translates into human benefit…so far. You asked about this one hitting the news

This week we have

Casella et al. Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice. Science Translational Medicine  2020: Vol. 12, Issue 568, eaba0599
DOI: 10.1126/scitranslmed.aba0599.

Now I can’t usually be bothered to report on these as they typically go nowhere, but I have decided to comment on this, on the off chance that the authors read their altmetric links and come to the blog.

They say “Multiple sclerosis (MS) is an autoimmune disorder characterized by neuroinflammation and demyelination. Administration of myelin-specific self-antigens to induce tolerance has been shown to be effective in mouse models. However, identification of disease-relevant antigens is difficult. Now, Casella et al. showed that oligodendrocyte-derived extracellular vesicles (Ol-EVs) contained multiple myelin-related antigens and tested their potential therapeutic effects; in multiple rodent models of experimental autoimmune encephalomyelitis (EAE), Ol-EV administration restored immune tolerance and reduced disease pathophysiology. The results suggest that Ol-EVs might be an effective approach for MS“.

So big words for something that will go nowhere if they do not learn.

What did they do?

Autoimmune diseases such as multiple sclerosis (MS) develop because of failed peripheral immune tolerance for a specific self-antigen (Ag). Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven effective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. One such approach is intravenous tolerance induction by injecting a myelin Ag used for triggering EAE. (Yep totally agree) However, the translation of this and similar experimental strategies into therapy for MS has been hampered by uncertainty regarding relevant myelin Ags in MS patients (Yep totally agree). To address this issue, we developed a therapeutic strategy that relies on oligodendrocyte (Ol)–derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags (The technology). Intravenous Ol-EV injection reduced disease pathophysiology in a myelin Ag–dependent manner, both prophylactically and therapeutically, in several EAE models. The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive CD4⁺ T cells (The biology). Furthermore, we showed that human Ols also released EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy. These findings introduce an approach for suppressing central nervous system (CNS) autoimmunity in a myelin Ag–specific manner, without the need to identify the target Ag (OK did they read our and others papers? This concept is not new).

So they took myelin producing cells and made myelin and then injected it intravenously and it inhibited EAE….Cure….Yeah

The mechanism is new as was “mediated by monocytes, as they up-regulate program death-ligand 1 (PD-L1) expression in an interleukin-10 (IL-10)–dependent manner, leading to apoptosis of encephalitogenic CD4⁺ T cells”. 

Does this mean T regs are falling out of favour?

Now I have to say this experiment has been done over and over again for over forty years. I started doing this in 1980s, my old Boss did it in the 1960s.

In my science life, the mechanism to cause this effect has been B regulatory cells, CD8 T suppressor cells, Th2 cytokine producing cells, anergy of the T cells, death of the T cells in the thymus and the blood, then T regulatory cells, and back to B regulatory cells and now macrophage-induced control. It has been going on so long that even some of my colleagues forgot their own work and changed the mechanisms with each immunological FAD

In this approach they made oligodendrocytes that produce myelin. They found that these cells made blebs of oligodendrocytes that contained myelin and then used these to turn off EAE in mice.

Now my advice from a jaded old mouse and comment.

Ok you will call me an A hole….but I am trying to be constructive…The level of disease inhibition shown in these different experiements are simply not good enough. Good enough for a publication yep, but pants in comparision to what you can done and importantly what you needs to be done in humans. You can completely eliminate disease if you want of a single injection

If you want this to work well in humans and even mice you have to deplete the CD4 T cells first and give the antigen after. If you start too late it is not going to work. Yes we have “been there, done that” and the result were far better than reported here.

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 Aug;165(1-2):41-52

I could say this to the face of the authors, indeed I have to others in the past and then watched them ignore the advice and then watched their trials fail. No wonder I’m jaded. Maybe the altmetric link will allow then to avoid the shock of this challenge to their authoritah

We too can cure mice if we treat them quickly enough, by a simple procedure (a) We deplete the T cell causing the disease and then we immunologically tolerise the brain-specific T cells that cause the disease as they return. (b) We do this by giving them the causative antigens intravenously and only needed to do it once, so it turns off the pathogenic cells. You can give the mice a brain mush and it picks out what is important to the mouse and you don’t need to know what is the causing antigen. It doesn’t have to be the same target between different individuals and at different times in disease.

Now the problem is that the scientists have convinced themselves that one size fits all and that you can use a few peptides to treat all of MS.

This fails in MS….As this paper suggests, it is unlikely that myelin basic protein or myelin oligodendrocyte glycoprotein are the sole problems, so wrong antigen.

My Colleagues don’t agree and continue to use this or that single protein. We have trial upon trial of failures. I thiink it will never work as it is not one protein for every body.

Take 5 different mouse strains where each strain is genetically identical and each of them responds to different proteins at different time so outbred humans are never going to responsd to the same target. The trials will fail…it is not rocket science.

Use a gemisch of antigens. It was used when people were asked to eat cow brains in the 1980s….. However, should not take long to think why this is a no-no now. You wouldn’t want to transmit mad cow disease. It didn’t work in MS, but it was never going to work, as eating the proteins were never going to be good enough. It doesnt work well in mice not surprsing it didnt work in humans.

So how do you make the proteins. You could make them using gene therapy and get cells to express the different nerve proteins and use these to switch off the immune response. Proteolipid protein is like brick dust and is a terrible protein to work with but it is the most important in controling disease for some strains. But the proteins are unknown in humans

However, you can do this.

In fact it is perhaps the best use of stem cells. You can make myelinating cells. We did this and we could get it to work, but we were not convinced enough protein was produced for it to work well and if we stuck brain protein onto the cells it could work perfectly.

We have not got the energy to try and set up companies to do this and it is doubtful that we can get the investment as the SH1 of the failed trials has stuck and the patents will stop new ideas.

However, with this backdrop I was interested in the paper today maybe they can give enough,

(b) To stop disease you have to deplete the T cells first and as they return you switch them off. Both approaches have been used in MS and are safe but doesn’t work . But thee tools to do this are not readily available and this is why people ignore us, at least one of the reasons.

MS is the wrong disease to try this approach as there are too many unknowns, but I guess you just have to try and do it. This reminds me to submit that paper its been sat there over lockdown.