Intravenous Tolerance study indicating autoimmunity in MS

van Noort JM, Bsibsi M, Nacken PJ, Verbeek R, Venneker EH.
Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial. PLoS One. 2015 Nov 23;10(11):e0143366.

As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5.

It has been shown that HspB5 is a potential target for autoimmunity and delivery of HspB5 via the tolerogenic route can reduce the number of MRI lesions by three quarters although the groups were too small to see an impact on relapsing disease. So is this the evidence that MS is due to autoimmunity to HspB5. I guess we should say yes.

There as many immunologists that think that the autoimmune target is myelin basic protein (MBP), which is easy to make and work with. 

This is not a good reason why this is a sensible target and there may be more holes in this hypothesis than a piece of emmental. MBP is present in the peripheral and central nervous system, and so it is perhaps not surprising that MBP-specific T cell receptor transgenic mice get peripheral neuritis (disease of the peripheral nervous system) as do some people with MS when immunised with myelin basic protein. Whilst there can be some peripheral nerve involvement in MS, this is not what MS is known as…a CNS related disease.

But if you think MS is autoimmune and you ask what does the immune response react to in an MS brain? It was found that it was alpha B cyrstallin (HspB5) and not any of the myelin proteins was the target for autoreactive cells in MS brains. It was found that people without MS could also respond to this protein too, but in healthy brains HspB5 was not expressed. It seemed that HSP5 was not expressed in the human thymus unlike in monkeys and rats and some mouse strains were it was expressed such that it would cause deletion of HspB5 reactive cells and so be relatively unique to humans. So in humans HspB5 reactive cells could escape thymic killing and escape into the blood and off they would into lymph glands waiting to get stimulated. Then viruses, notably EBV, would infect B cells and they would express and present HspB5 to T cells causing their priming and then you have everything ready for an autoimmune disease. Then something infects or stresses the oligodendrocytes and they them upregulate HspB5, which they do, such that it becomes the most abundant protein expressed and a target for autoimmunity. 

So simple turn off the immune response to HspB5 and that is the end of MS! 

Furthermore as HspB5 is a heat shock protein and molecular chaperone it should be neuroprotective and delivery of the HspB5 protein in EAE has been suggested to be an “immunological brake” So deliver it to MS and there should be neuroprotection and it should cause immunological tolerance when injected intravenously. 

So this is a very nice concept and has few limitations except that MS should also cause a lot of lens problems as HspB5 is expressed in the eye and one wonders how much protein will actually get to the CNS to be a microglial inhibitory molecule via Toll2-like receptor?

Anyhow, now this study reports that gadolinium  responses were reduced as were the T cell responses, but they were not eliminated. So is this the start of something good? If this does not get developed will it be the end of a missed oppertunity as the best chance to control autoimmunity in MS using antigen-specific therapy, which should have limited side effects. The future now depends on whether there are larger Phase II or Phase III studies. 

We have been saying for some time that intravenous tolerance works best when it is applied following CD4 T cell depletion. Would this have got rid of more lesions, T cell responses and importantly relapses as 1/4 (low dose), 1/7 (medium dose) and 3/7 (high dose) people relapsed and could point to failure of the project. However it surely does suggest that there is an autoimmune process in MS. 
CoI. ProfG was on the advisory panel 

About the author



  • It doesn't really matter what the target autoantigen is or if the autoantigen changes over time. All people have autoreactive cells that react to MLB and I suspect this is the same for every tissue in the body.

    Since the introduction of immunosuppressives it really doesn't matter any more. The quest for looking for the autoantigen is over as no drug company would invest the time or resources to study this further with the market swamped with cheap immunosuppresives.

    The future of MS research is to stop progression by shutting down the chronicily activated innate immune system as well as repair mechanisms.

    • So you say stop anything to do with relapsing MS?

      Because it is all sorted and after the current crop come out of patent you will be left with them forever. You will be happy with your PML those autoimmunities the hair lost the runs the flushing the birthdefects the lipid loss the flu the heart problems, leukaemia risk.

      However you may be right once the bottom of the market drops out and pharma will be off.
      Who is going to spend loads of millions to do the trials. MS societies cant afford to do them to the quality that pharma do them now.

      Maybe Merck should stop theiri study in MS with their MBP peptides and throw away the hundreds of millions invested run before they loose anymore. The chicago group should throw them beads away and them dna therapists are wasting their time.

      The above can defend themsleves and if it is a turkey it is a turkey, some of them may be however this type of treatment is going to be what you want for progressive ms. A drug free environment on which to layer your neuroprotective and repair agents.

      You may be right but this is for all the wrong reasons.:-(
      The best way to stop progression is to not let it start in the first place. Antigne specifc tolerance can do this.

    • Exactly MD, from what I've read about tolerance to specific antigens may be yes s final output as a treatment not only for MS, as for other autoimmune diseases. So in my humble opinion more research area should continue …

    • I never said I was happy, I'm just speculating that antigen specific tolerance therapies will not be pursued in the future. This would be in my view a true cure for someone who is newly diagnosed with RRMS.

      But I don't see this route being pursued because when the immunosuppressive drugs such as Fingolomod comes of patent and cheap generics can be made who is going to pay for a antigen specific therapy? There will no longer be a market for high cost MS drugs.

    • "But I don't see this route being pursued"

      You may be right for any new treatment and we will have to put up with what we have now

  • Re: "Then viruses, notably EBV, would infect B cells and they would express and present HspB5 to T cells causing their priming and then you have everything ready for an autoimmune disease. Then something infects or stresses the oligodendrocytes and they them upregulate HspB5, which they do, such that it becomes the most abundant protein expressed and a target for autoimmunity. " In people without MS they could respond to this protein but in healthy controls it is not expressed. Is the loss of tolerance to HspB5 the issue or is dysregulation of HspB5 expression due to chronic infection the culprit?

    • magine you have 500 cells to tolerise and you try and your tolerance mechanism can turn off 350 cells you have 150 cells to deal with that aren't controlled. Now use CD4 antibody to kill 80% of the cells and now you have 100 cells to deal with add your tolerance and so it can deal with all of them. Simple as that so rocket scieence and it works time after time after time as we have shown in animals. (Pryce G et al. 2005)

    • Why does the total number of cells to tolerize matter, rather than the fraction of all available cells? What you describe sounds like "titration" – but should we think about thermodynamic control instead? In each scenario, prior depletion may be beneficial.

    • Do it as a fraction you have a tenth of your ceĺls to tolerise the tolerance only can get a twentyth. You could titrate the tolerogen up perhaps but there is a limit in the trial in humans they were transfering 300 000 000 cells to do it and still needed more.
      Thermodynamic control i dont understand what temperature has to do with it.

By MouseDoctor



Recent Posts

Recent Comments