Should we be ignored, disproved or whitewashed? Autoimmunity after alemtuzumab

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Last year we suggested that a problem with alemtuzumab was that it failed to adequately deplete immature B cells in the bone marrow. These cells rapidly re-populate the body after depletion and this leads to a hyper-repopulation of B cells. Importantly, and different from ocrelizumab and cladribine, which both deplete B cells, this occurs after alemtuzumab in the relative absence of T cell regulation. This may allow B cells to escape immune tolerance and so may allow secondary autoimmunity to develop.


Where should we look to find the reason behind this?

Pharma is still suggesting that alemtuzumab increases CD4 regulatory cells based on that written in label from the European regulators. However, in my opinion it is an error of data interpretation!


This is because the absolute numbers of T reg cells plummet. Based on percentages relative to the CD4 population it has been argued that there is a 13% increase in Tregs. However 30,000 cells per mL down to 2 cells per mL is clearly not an increase! 


This would become important if the cells that need to be regulated are B cells and not T cells. So whilst T cells are deleted massively, the number of immature B cells dramatically increase, in the blood at least, and so the ratio of T reg to immature B cells drops and so there would be less regulation of B cells. 


Since we made the suggestion, there have been attempts to discredit /disprove this view. This was dismissed previously, because of belief of the increase in T regs after alemtuzumab. 

This I suspect will be on show at ECTRIMS 2018.


Paper

P880 – H. Wiendl, D. Brandes, M. Carraro, G. Comi, Y. Mao-Draayer, G. Izquierdo, H.-J. Kim, S. Meuth, G. Pardo, B. Sharrack, C. Tornatore, T. Ziemssen, A. Jacobs, L. Chung, N. Daizadeh, B. Van Wijmeersch, on behalf of the CARE-MS I, CARE-MS II, and CAMMS03409 Investigators H. Wiendl. No correlation between lymphocyte pharmacodynamics and autoimmune adverse events following alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis.
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I guess it will report that development of autoimmunity does not correlate with the level of depletion levels of Tregs. In case the poster has not yet been written.

I say “so what”. Our animal data suggests it is cells within the CD8 population not the CD4 population, so “who cares what’s found in the CD4 Treg population?” 🙂 


However, people will say that the level of CD8 T cells do not correlate with disease activity either.

But again “so what?”  “Who cares about the effect on the general CD8 population?” :-). We have to be interested in the specific population of cells causing the regulation. 


There is no way the phenotyping in the MS CARE-I & II was detailed enough to address this properly; I have seen the panel of antibodies used. Likewise when do you look for an effect? A few months before the autoimmunity or a few years?


Whilst I do care about the above and am just being flippant:-), I would say it is most likely the blood is the wrong place to be looking when we are considering where and when autoimmunity occurs. 


So if there was an effect in blood it would have been good, but if you can’t find one you are either not looking in the right way or it is not there.


We know that relapses can occur in arthritis after treatment with rituximab, when there are essentially no B cells detectable in the blood. Perhaps the bone marrow of the lymphoid organs ,which contain about 70% of the lymphocytes compared to the 1-2% in the blood.

However, this is all missing the point. 


The fact of the matter is that when B cells repopulate they do so in an environment deficient in T cell regulation.


This may well be the critical reason why people develop autoimmunity. 


This is the hypothesis. How do you test it?


I am sure there are people who do not develop autoimmunity who will also have developed B cells in the absence of T regulation. Surely, there is more complexity to the development of autoimmunity than the simple depletion of one cell subset. 


In the past it was suggested by others that Interleukin 21 (a cytokine that does a number of things but is produced by T cells that help B cells) and lack of T cell regulation may be important.


Indeed something is important as many people treated with alemtuzumab are developing secondary antibody mediated autoimmunities. If these could be avoided then alemtuzumab would be an even better drug than it already is.


Therefore in this context I think we should all read this paper, because it has been reported that when immature B cells are formed (in the bone marrow) the vast majority of B cells have the potential to be autoreactive indeed. In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity (Reactiviety to self -autoimmunity). 



Paper

Wardemann H, et al. Predominant autoantibody production by early human B cell precursors. Science. 2003;301:1374–1377


During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation in human B cells. A majority (55 to 75%) of all antibodies expressed by early immature B cells displayed self-reactivity, including polyreactive and anti-nuclear specificities. Most of these autoantibodies were removed from the population at two discrete checkpoints during B cell development. Inefficient checkpoint regulation would lead to substantial increases in circulating autoantibodies.

  • “More than half of the antibodies expressed in early B cell compartments are polyreactive (reacts with more than one thing) and suggest that nearly 90% of the polyreactive antibodies are counter-selected in the immature B cell stage”
  • “The number of human B cells deleted during development is not known, but in the mouse it has been estimated that 80 to 90% of all newly produced B cells are deleted before they enter the mature B cell compartment”
  • “In the bone marrow the immature B cell stage is one of two important checkpoints for selection against autoantibodies.The second checkpoint for selection against self-reactive antibodies in humans is at the transition between new emigrant and mature B cells in the periphery”

The authors conclude that “during normal human B cell development, large numbers of self-reactive antibodies are removed from the repertoire during the immature B cell stage in the bone marrow, as well as during the transition from the new emigrant to the mature naïve B cell stage in the periphery”.
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Would you want to be generating these cells when there is no T cell regulation? I’m not sure I would.


I suppose you can look for the simple route to the problem, or ignore it and look for something more complex.


However, I guess the “T reg story” was developed as a way to show how alemtuzumab may stop MS in the light of current dogma. “The pathogenic cells repopulate at a time when there is more T regulation, so no MS”. This idea perhaps holds true as the CD8 populations are back to normal levels within 6 months and memory CD4 and B cells are gone for over 2 years. There was no mention of autoimmunity with regard to T regs, so one didn’t need to think about how secondary autoimmunity developed


However, should it be surprising that losing CD8 and T reg cells during a time, when immature and mature B cells are expanding could be involved in secondary autoimmunity? Is this too complex a link to follow?


Am I being thick?


If true there could be solutions, but is it too late to start thinking of them?

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MouseDoctor

7 comments

  • Just give patients Ocrelizumab after Alemtuzumab. Maybe we have a cure for MS. But great article MD. Barts at it's best.

  • been thinking this for a while maybe its time to think multiple treatments as a way of halting MS progression two doses of Alemtuzumab then a few doses of Ocrelizumaba starting 6 months after the last dose of Alemtuzumab
    let see what come out at ECTRIMS 2018

  • maybe this is the time for dual treatments??? give a few doses of Ocrelizumab 6 month post the second dose of Alemtuzumab.
    I sniff a trial

  • I'm with you on this. I believe it is lost on many that more than 1/4 of mature B cells exiting the bone marrow are auto-reactive to some degree.
    Need those T cells!

  • Why do many who are treated with Alemtuzumab not get secondary autoimmunities? What is different about them or their MS?

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