If we believe that MS is an autoimmune disease, then the best way to treat it is to induce immune tolerance to switch-off the disease-causing cells. This should have essentially no side effects. There have been many attempts in MS and all have failed, but it can be done in EAE.
It may be possible to do it in MS, as indicated here. If you are glass half-full person maybe stop here and jump to the story at the bottom, half-empty and interested to know why I am cynical and don’t like dogma. Read-on.
In MS you don’t know what the disease-causing cells are reacting to. We looked in an animal mode,l where we didn’t know what was causing the autoimmunity and we seemingly cured the mice within 24 hours, if we started early enough. If we left it too late when there was secondary progression all we did was get rid of the relapses
Was it rocket science….No.
It was simply immunology 101….We followed an approach that was developed in the 1960s that had been used to get rid of skin disease (allergy to chromium) in guinea pigs.
We did it in mice and then spent many years trying to get the idea published in a top-flight science journal.
The problem was that it worked, but there was no single, simple mechanism to explain it and those mechanisms we found “weren’t the flavour of the year”. In addition, because we did not orignally know the pathogenic antigen (Target for the immune response) and could not measure T cell proliferation, the T cell immunologists weren’t interested…..It was repeatedly immunologied away….Slipping down the greasy publication pole, wasting 5-6 months for each journal that we submitted to.
I was chumbawamba publishing. For those of you who don’t know who they are. They were in my humble opinion abit of a band who were essentially a one-hit(Tubthumping) -wonders.
Anyway, we presented the idea at a few meetings. I remember this European science Demi-God reading the presentation called a poster at a small demyelinating meeting in France. A year and a bit later the same idea arrived, as a new idea, using a simple sexy science system (T cell transgenic system) that meant nothing for any disease, but it was in a top-flight journal. I guess “Snooze and You lose”..in the publication stakes.
We did more an more and there was not going to be a T cell proliferation assay and we evenually thought lets get it out and the work surfaced in 2005, with a slightly different message. No wonder I’m a grumpy old git and thats only half the story.
Anyway now I have got that is off my chest
There are many ways to induce immune tolerance, but the most robust way of doing this is by giving the pathogenic antigen by a tolerogenic route. The simplest route is the intravenous route. This approach works in most people’s hands, unlike some other approaches like eating the antigens (Things the immune cells react to). However, you have to know the causative antigen. We know that these vary between different individuals and they change with time.
So how is it done…Simple you give whole brain tissue intravenously and the individual’s immune sysem selects what is important to it and these responses are tolerised (Immunologically-switched-off). So we did this in autoimmunity in mice, where we did not know the causative targetbut we knew the target was in the brain tissues. We delivered this to turn off the brain related autoimmunity and we worked out what the target antigen was.
We did this by gluing the brain proteins onto dead cells or beads Easy Peezy….but now the problem 1….Along came Mad Cow disease and now you were not going to be easily able to use human or animal brain tissue to put into humans, because of the fear of transfering something infective.
Alternatively, you could make protein and we did it, but we were working with a protein that was like brick-dust and wasn’t soluble in water and formed protein blobs in solution. You needed a create a factory to make this for human use. But how many proteins would you need to make. Well not as many as you may think as long as you get the important ones and we did it with one
However, whilst it was easy to do this and stop disease from starting a bit like a vaccine, it didn’t work well enough if you already had disease…However, no problem you go back to immunology 101 from the 1960s and it tells you that you have to deplete the T cells and as they recover you given them the intravenous protein and you get the “weed killer effect”. It partially activates the disease-causing cells so they die or switch off and it induces suppressor cells that regulate any surviving cells. Some weed killer make the plants grow to death.
Now problem 2. How were you going to deplete the T cells. This would have been easy if we had done the work ten years earlier because companies had manufactured anti-CD4, which didn’t work in MS and didn’t work well in the animals either. However, all the companies had stopped making it and they wouldn’t start to produce it (A large amount of effort wasted trying to encourage people to do this). Had we thought about it we could have tried anti-thymocyte globulin but luckily, we didn’t because we later showed that alemtuzumab-like drugs, blocked the tolerance from forming so that was no good. It was blocking the action of a CD8 T cell required for the tolerance to develop
Now Problem 3. This is MS. We don’t know the antigen causing the problems. Some people think it is myelin basic protein. This is my opinion not a good choice. MS is a CNS-restricted disease Myelin basic protein is expressed in the peripheral nerves so why not more peripheral neuropathy in MS?. However, intravenous myelin basic protein was tried and it failed.
It was doomed in many ways (a) Myelin basic protein is the wrong choice, but the T cell immunologists love it because it dissolves in water and they can do cell culture and cell proliferation. Many people (opinion leaders) think that the important targest cause T cell proliferation. Many still do. However we found that the disease-causing fragments from about seven-eight different proteins in three of four differnt mouse strains and in two different diseases and in no instance was the fragment the caused the strong proliferation of T cells the fragment that triggered the disease. (So start with T cell proliferation and you end up with nice papers, but perhaps clinical blind alleys, but start from nothing and work backwards you find disease causing epitopes, typically no T cell proliferation and problems with the dogma machine who control the sciencific press 🙁 (b) They did not deplete the T cells so it was never going to work well and (c) They did it in secondary progressive MS and it is never going to work well there because it needs to be in relapsing MS. Yes I did tell them about the need for depletion, however they convinced themselves it was going to work and it makes the trials too hard and complicated to do. If you don’t own the rights to the depleting agent and tolerogenic agents you have problems and this is why monotherapies (single treatments) and not combinations are the norm….Anyway company doing the work disappeared…sunk without trace.
Alpha B crystallin (HSPB5) came alone, a much better target as most people agree it is upregulated in MS brain and is the major antigenic protein in the inflammed brain. It is presented to T cells by virally-infected B cells…Again, trail was done as a monotherapy. They didn’t do the depletion. Guess what?…..it failed.
THE POTENTIAL SOLUTION STORY STARTS HERE
ProfG came up with the idea that MS was too complicated a place to start. Did we know of a human autoimmunity where we know the antigenic protein and have a source of the protein that can be used in humans?.
The answer was yes.
Now there are more ways to get information into the public domain
Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosisMonica Calado-Marta, David Baker, Paul Creeke, Gareth Pryce, Sharmilee Gnanapavan, Gavin Giovannoni. medRxiv 2021.01.24.21250414; doi: https://doi.org/10.1101/2021.01.24.21250414
People with MS were getting beta interferon and this was causing an immune response that caused antibodies to neutralise the effect of beta interferon, so the drug stopped working. There were 3 types of interferon Beta to use, it was a human protein and the imune system reacted against it so it was a human autoimmunity where we knew the target. How could we induce the depletion. We could use an MS drug and we chose mitoxantrone which was being used in MS. One of our mates had tried to get rid of the anti-drug response with intravenous beta interferon, they didn’t deplete, so the study failed, but it gave us a safe dose to start.
At the time the alternative to a failed response to beta interferon was to swop to glaterimer acetate. If you neutralized beta interferon it stopped working and relapses could occurs so it was clinically relevant. However a beta interferon manufacturer gave us an unrestricted grant to do a study
However, problems arose and that was dealing with regulators and sorting out the anti-drug assay for the trial. We had to design it and bring it in-house and then get it approved for clinical use and a few years lapsed.
We started the trial.
By the time we had everything in place two bombshells dropped that killed us off. Mitoxantrone was shown to be more risky as it has a cancer risk. So we had to stop using it. Next there were alternatives. It was safer to switch some to a different drug, so ethically we could not continue and we canned the study. End of that approach.
What happened in the trial you can read here.
Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosisMonica Calado-Marta, David Baker, Paul Creeke, Gareth Pryce, Sharmilee Gnanapavan, Gavin Giovannoni. medRxiv 2021.01.24.21250414;
Background: Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFNβ1a) develop neutralizing antibodies to IFNβ1a that do not disappear in repeated tests over years. Methods: One PwMS was recruited, as part of a planned phase IIa trial (n=15), who had developed neutralizing antibodies to subcutaneous IFNβ1a. Mitoxantrone (12mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88μg/day + three 132μg/day) intravenous IFNβ1a. Subcutaneous IFNβ1a three times a week was maintained during follow-up. IFNβ1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months. Findings: One participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased. Interpretation: The data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted. Funding: The study was supported by an unrestricted research grant from Merck-Serono.
Yep the anti-drug response disappeared where we did not see that happen in 13 other people, was it a fluke? We will never know, we stopped the study.
We went back to the drawing board to see if we could get stem cells to make myelin proteins. We could get it to work a bit in animals (well better than most recent EAE studies) but the protein expression just wasn’t good enough in my mind. Others were doing the tolerance studies making it difficult to get support and were creating a patent enviroment that was not condusive for further company support, so we put it on the back burner, as we had other things to do.
However, is it Chumbawamba time again?
Opportunity Knocks. With the RNA vaccines we now might have a way to make the proteins without factories until it is ready to go into humans. These approaches are patent protected, it could be game on. But their data shows it doesn’t work well enough in animals with pre-existing diease. But I suspect it may do a lot better with the depleting step first. So it was time to get our data out of the moth balls, and describe again the immunological principals. This is what is important. Will they ignore it and plough on with monotherapy? I’ll send them a copy and it is up to them.