Breiden, S. Reinhardt, C. Schulze, M. Bester, C. Heesen, S. Schippling,
S. Miller, M. Sospedra, R. Martin. Induction of immune tolerance by autologous peptide-coupled cells – a phase I trial in relapsing-remitting and secondary-progressive multiple sclerosis patients.
The aim of this first-in-man trial was to assess the feasibility,
safety and tolerability of a novel tolerization regimen in MS patients,
that employs a single infusion of autologous peripheral blood
mononuclear cells chemically coupled with seven myelin peptides
(MOG1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170 and
performed in nine MS patients (7 relapsing-remitting and 2 secondary
progressive), EDSS 1-5.5, who were off-treatment for standard therapies.
All patients had to show T cell reactivity against at least one of the
myelin peptides used in the trial. Neurological, MRI, laboratory and
immunological exams were performed to assess the safety, tolerability
and in vivo mechanisms of action of this regimen. We followed the
overall patient immune response as well as responses to myelin antigens
prior to and following the administration of peptide-coupled PBMC.
favorable safety profile and was well tolerated in MS patients.
Compared to the pre-treatment observation period there was no increase
in clinical and MRI parameters of disease activity by this regimen.
Patients receiving the high dose (>1×109) of peptide-coupled cells
showed a decrease in antigen-specific T cell responses following ETIMS
peptide-coupled cells in MS patients, establishes the feasibility,
tolerability and safety of this novel therapeutic approach.
Why do I think that this could happen because I have seen this happen in the beasties, many, many, times
Many years ago when I was a PhD student I stated looking on antigen-specific tolerance induction. This means that it is a way of specifically turning the immune system off such that it no longer responds to your target of interest but does not interfere with the function of the rest of the immune system.
This had been also been shown in mice by a guy called Henry Claman and another chap called Steve Miller. It is funny that both Steve Miller and I moved onto working on models of multiple sclerosis.
People in Steve Millers lab showed that if you stuck the proteins that you use to induce disease onto white blood cells and inject them into the blood of mice it stopped you from inducing disease. It even worked if you had already sensitized the mice to get disease and so worked in a therapeutic context. This is the basis for the trial.
Now in mice you usually know what the the inducing protein or protein fragment is. This is because this is what you use to cause disease in the first place, so if you induce disease with a protein fragment (a peptide) and then you inject that fragment intravenously it can inhibit T cell-driven autoimmunity. This is a very consistent finding throughout immunology, so there are no special tricks. It is a fact of biology.
- The treatment is unlikely to work for non-gadolium enhancing/relapsing PPMS/SPMS. Why? This approach has failed in non-relapsing progressive EAE, where is it is essentially 100% effective against relapsing EAE, more on that later, and intravenous myelin basic protein (which contains all the peptide fragments of MBP) has failed in secondary progressive MS already.
- The peptide fragments that cause the disease will be different for different individuals and this may change as disease evolves. If the peptide fragments that cause the disease are not in the cocktail stuck to the white blood cells it will not work. If the peptide fragments are not the dominant driver of disease it may be less effective or not work.
- Now Dr Miller has reported that this approach induces what ever mechanism of action was dogma at the time of the experiment and includes CD8 T suppresser cells, Anergy-cell unresponsiveness, CD4 Th2 suppression and T regulatory cells etc. However, in virtually every immunologists hands the mechanism is specific to the target injected intravenously. So if it is not there in the cocktail of fragments then the approach fails.
- You probably cannot use a gemish of brain antigens as you can in animals. Use of human brain contains all possible targets. But as a gemish it has problems because of the fear of passing on human brain disease such as human mad cow disease. This has the advantage that you do not have to know the causing fragment you just give the immune system every thing and it works out what is interesting. On the plus side if you are lucky and control the dominant immune response it can be active despite the presence of autoimmunity to other minor targets.
- The problem may not be caused by autoimmunity, but we know it is an immune problem because relapses respond to immunomodulators. However, MS may not be a problem of autoimmunity to myelin antigens. If this is the case the approach will not work because the wrong peptides have been selected. There is another study that is using the intravenous approach against a non-myelin antigen which is ready for phase II already.
- They are injecting the target into an established immune system. This approach works quite well when the individual is not yet sensitized but is does not work as well as it should when the immune system has already become sensitised, which would be the cause when using in MS. Therefore, it may not work or give you a partial answer such that it works for a while and then disease returns
- We (Team G) believe that they should deplete the T repertoire before delivering the the intravenous target. This should be done when the immune cells are recovering from the depletion and it causes a re-education of the immune cells such that they are no longer self aggressive. However depletion of immune cells in MS has already been done and this approach is safe so if you put this current approach with the deletion event you can make the two approaches, which are not optimally effective when used individually and completely stops relapsing disease when used in combination.