This new article is really a blast from the past and the work was done a few years ago. However, when the makers of the COVID-19 vaccine came up with an idea to cure MS with a vaccine. I wrote to them to say that their data was not as impressive as it could be and that if they wanted it to work they really needed to deplete elements of the immune-response first.
I recieved no response and so if this vaccine goes further, as they certaily have enough money to do it, I will wait to see what happens.
I guess too big to respond to the plebs:-(
Anyway this spurred me on to dust off the cobwebs and get the work from out of the archives
We have been switching-off the immune response for years and we are very good at it.
If we have Mr.Mousey with their MS-like disease we can switch off the relapsing attacks within a few hours no matter if it a black mouse, a white or Brown Mouse and the the autoimmune disease would be gone for good no matter when we started treatment even ages after disease onset
Yes gone! Not some rubbishy small diminution of the clinical signs and a few days delay that we frequently see…
I mean the “Cillit Bang” of Disease Control. One injection (actually two) and Bang! Autoimmity is Gone.
This is why I am so cynical about “EAE cure of the week”. I know what is possible and also believe that many of these “Cures of the Week” would not translate into treating decent disease in another animal, let alone a human.
This is the problem…. a small effect is enough to convince your mates that you have found a mechanism of interest to get their paper in Impact factor blah de blah…but the effects are not good enough for them to be a real treatment.:-(
In terms of tolerzing the beasties we have done this hundreds of times with few failures. It is reproducible and does not require special “green-fingers” to get it to work. The protocol is out there anyone can do it…..OK it helps to have MD2s paws and eyes for injections
We didn’t even need to know what was the cause of disease for a long for a long time…we didn’t care we knew the disease-causing driver was in the central nervous system and the treatment was specific to the disease causing cells and so would have few or no side-efffects.
We went backwards to work out what was important we used a single peptide and sensitived with a mix and low and behold it was an antigen that did not cause a T cell response in a test tube. Indeed essentially all of the major pathogens we have ever found to drive differnt diseases in beasties do not cause strong T cell responses.
Therefore, it is of interest that the targeted for human disease control are all based on their capacity to cause T cells proliferation.
In humans, we don’t know what antigen(s) cause(s) MS. Based on studying mice it is likely that different people will have different drivers.
This didn’t matter to us….as we didn’t know the cause of the antigen driving the mousey-disease either, but you get round this by supplying a mixtutre of antigens. Mr Mouse’s immune system selects what is important to it and it may not be the same as another Mr Mouse. It would be easy. We would turn of the responses to the whole brain “gemisch” or a few proteins. But if you used a few proteins you had to guess wisely and hope you have the problem target
However, then came along “mad cow disease”, which meant that we were never going to be able to use brain tissue to switch things off. This approach had been tried in MS, where they feed people with MS some cows brains…The approach didnt work in humans….but hey it was probably never going to work because it didn’t work in mice with disease either…. when we tried it. The experiments justifying the human trial largely fed the brain tissue before the disease started rather than the harder task of feeding after disease onset. The former is really simple to control however it is much harder to switch off once started. The reason being was that you probably have too may bad cells to get rid off.
The solution was you have to deplete the lymphocytes and as they start to recover you give them their target antigen in a tolerogenic way and the immune response is switched off and the naughty cells die (I call it the weed-killer effect. The weedkiller stimmulates the plant to grow and kill itself) or are regulated…..Simple.
Well yes it was that simple, my old boss had done this in the 1960s in Guinea pigs with skin diseases, we had done it in mice as had others after they saw our work. It was robust in animals. Could we do this in MS? All the components we wanted to do had been tried in an MS and had failed just like they did when done when used alone in the beasties.
You could plough-on and do a trial in MS, but if it failed what would you learn as you don’t know what the autoimmunity is caused by and you would only know there was autoimmunity if it worked..
ProfG came up with the idea of this where we know that autoimmunity to a human protein occurs, we know what the antigen is and it can be administered to humans.
Which antigen? Yes the humble interferon beta.
Beta interferon would inhibit MS but if you make an immune response against the beta interferon it neutralises the beta interferon and so it stops working and relapses occur. It is autoimmune because the protein is a human protein, some may disagree but they are splitting hairs, So let’s get rid of the interferon response.
So we induced a transient immune depletion and gave the beta interferon intravenously, which is a tolerogenic route, and surprise surprise the immunity to the beta interferon disappeared. If you just give beta intravenously it doesn’t get rid of the response. So what we saw was very, very, very unusual. This case was part of a big trial planned, but then came the spanner in the Works. (yes this is British Slang so I have given you a link to explain it)
The depleting agent we used was mitoxantrone as we could not get what we wanted, The agent we wanted had been used in humans but it was in storage (mothballed) and the manufacturers didn’t want to revive it/them. We used mitoxantrone as it was an MS depleting drug that could be used in MS. However, during the time the trial was done it became evident that mitoxantrone had cancer risks that weren’t evident when we planned the study. So this was a problem.
Importantly, other MS drugs became available and so you could switch people to them and so not expose them to an experimental procedure. Furthermore mitoxantrone would be a risk factor for brain virus disease (PML) for anyone taking natalizumab. So after glorious success the trial was stopped and we did not recruit any more people and so we closed it and went back to the experimental drawing board. If we wanted to try MS we would have to get a new depleting agent and an mixture of antigens.
To be honest given the range of treatments, MS is no longer the best place to develop this further, it would be simpler to do another disease where the pathogenic antigen is known.
However, we tried CD52 as a depleting agent in the beasties…but that sent us off looking for anti-drug antibodies and it showed that that it wasn’t the right way to go as it depleted cell subsets that we needed for the beneficial effect, but in our mind helped use to understand the autoimmunity issue with alemtuzumab.
We did some other things involving stem cells, but I will tell you about this on another day when that is written up.
However the combination approach will probably be a barrier to this happening in MS. This is because there will be patent issues to contend with and people will only have the rights to the antigen delivery and not the depleting agent. Furthermore it makes the trials more difficult. I have already seen this happen leading to failure and it could be happening again right now, but that’s another story.
Anyway we have put the approach out there and maybe people will take note, otherwise they will probably continue to throw away their chances of success. A manufacturer of the preferred depleting agent is now in the MS space, get the tolerance approach and you never know…although I suspect I do. Their may be others too. The new vaccine technology may make it easy to make the antigen
However doing this in advanced disease in the beasties, it did tell us that you need something different to control progressive disability and said treat early and effectively
Have a read
Marta M, Baker D, Creeke P, Pryce G, Gnanapavan S, Giovannoni G. Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosis: A case report. Mult Scler Relat Disord. 2021 Oct 1;56:103284. doi: 10.1016/j.msard.2021.103284
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.
General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.