Full Filling your Wishes. CD52 depletion and maybe reasons for autoimmunity


Depletion of CD52 positive cells inhibits the development of CNS autoimmune disease, but deletes an immune-tolerance promoting CD8 T cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosisStephanie von Kutzleben, Gareth Pryce, Gavin Giovannoni, David Baker  Immunology doi: 10.1111/imm.12696 Accepted manuscript online: 7 December 2016

The objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction via intravenous antigen administration such that it could be used to either: improve efficiency of inhibition of MS or to inhibit secondary autoimmunities that may occur following alemtuzumab use in multiple sclerosis. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses assessed clinically. A dose-response of CD4 mAb depletion indicated that 60-70% functional CD4 T cell depletion achieved in perceived failed trials in MS, was perhaps too low to even stop disease in animals. However, more marked (~75-90%) physical depletion CD4 T cells via CD4 and CD52 depleting antibodies inhibited relapsing disease. Surprisingly in contrast to CD4 depletion, CD52 depletion blocked robust immunological unresponsiveness via a mechanism involving CD8 T cells. Although efficacy was related to the level of CD4 T cell depletion, the observations that CD52 depletion of CD19 B cells was less marked in lymphoid organs than in the blood provides a rational for the rapid B cell hyper-repopulation that occurs following alemtuzumab administration in MS. That B cells repopulate in the relative absence of T cell regulatory mechanisms that promote immune tolerance may account for the secondary B cell autoimmunities, which occur following alemtuzumab treatment of multiple sclerosis.

Recently someone on the blog was complaining about TeamG research output when we posted on our paper about what to call some one with MS

You said

“What causes progression and how can it be treated, making Alemtuzumab safer and more effective, encouraging them brain to kick-start repair…. so far Team G is in wizard of Oz land – big voice, until you pull back the curtain. Time for some real research Team G!”

To address your comment how do you make “Alemtuzumab safer and more effective”  

You have got your wish.

To ask how you make alemtuzumab safer, you first have to understand why it is not safe and to have ideas. 

You have to have the data, but it does not always easily come to hand or do you have to do some detective work?

The safety issues relating to alemtuzumab are: 

  • infusion reactions, 
  • consequences of long term blanket immunosuppression and
  • secondary autoimmunities that occur in about 50% of people within five years. 

How do you get rid of all those problems?…Simple!.

Use another drug that does not have these problems…

However, to be serious….Ask the many people who have had great benefit for the alemtuzumab and I am sure they will say it was worth it.

However to get rid of the safety issues you first need to understand what they are and how are they caused.

We know how to turn off an autoimmune response within a day in the beasties. To do this we simply reduce the T cell number and then re-induce immune tolerance by intravenously injecting the target antigen. Sounds simple…it is.

The way we do this is deplete CD4 T cells but we asked the question is could we use CD52 depletion instead?

Why? Because we could not get anybody to give us access to a CD4 depleting 

However, the answer was surprsingly no.

We found essentially three things

(a) CD52 depletes CD4 T cells and inhibits relapsing EAE

(b) CD52 depletion did not deplete B cells in lymph glands as much as it did in the blood 

(c) It blocked the development of unresponsiveness in our hands and this was probably because it depleted a CD8 regulatory T cell population that was inducing tolerance.

What does this mean?

(a) If MS is caused by CD4, Th1/TH17 T cells then these will be inhibited by alemtuzumab…

(b) The problem with alemtuzumab is that it causes B cell autoimmunities like Graves Disease (hyperactive thyroid disease), ITP (blood clotting problem). This means you have have blood tests every month for 4 years……

So if the antibody that does not clear B cells out lymph glands/bone marrow it means that once the antibody disappears ,which takes about a month then B cell, that have escaped destruction can rush out of the lymph glands and they can then fill up the blood with new cells and they can overshoot…This is the elephant in the Room.

When the B cells repopulate they are doing so when there is a limited T regulation, in this case a CD8 T cell population, which is destroyed by the CD52 depletion. These used to be called CD8 T suppressor cells. So is this the reason why people with MS get lots of secondary B cell autoimmunities…Prompted some delving and it was found that not only was B cell autoimmunites a problem but anti-drug responses occured with staggeringly high frequency. 

Do they affect treatment response?

However, it pointed us to places that allowed us to understand how alemtuzumab-probably induces autoimmunities and works in MS,
But that’s another story to be reported soon

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  • this was a really good read. I truly appreciate the data presented here. Maybe I'm being daft but the logical question I come up with is whether or not there is a treatment/medication that can be used immediately prior to Alemtuzumab to entice the B cells to leave the lymph organs and reside in the blood stream so that Alemtuzumab can knock them out?

    As a corollary comment/question for those who theorize that MS is a B-Cell driven disease on the hypothesis that EBV is residing in the B-Cell population — is the lack of complete B-Cell knockout note about supporting evidence for this?

    • We subscribe to the hypothesis that DMTs, including alemtuzumab, are targeting EBV-infected B cells. Targeting this pool is our aim.

      With regard to secondary autoimmunity the aim is to prevent the B-cell hyperproliferation occurring in the absence of T-tell regulation.

    • Anon 1:36 Glad you enjoyed it. This is the first in a series on the subject, the rest will focus on the clinical situation, which will be even more revelatory.

      "With regard to secondary autoimmunity the aim is to prevent the B-cell hyperproliferation occurring in the absence of T-tell regulation."
      Use cladribine instead 😉

    • You could also reengineer CD52 to do this, or use a different treatment regime, when ocrelizumab and rituximab was tested therte was often an infusion a few weeks after the first.

  • Is it possible to explain, where is the 'memory' in the immune system? Is it solely in the mature B cells or somewhere else? If all B cells were to be knocked out, would the patient be immuno-naive?

    • In B cell terminology the Mature B cells are actually naive B cells, there are different populations of memory B cells, incuding switched and isotype (of the immunoglobulin e.g. IgA, IgE, IgG) unswitched.

      We know that B cell memory survives alemtuzumab because you don't need to revaccinate against the common viruses for example

  • "However, it pointed us to places that allowed us to understand how alemtuzumab-probably induces autoimmunities and works in MS,
    But that's another story to be reported soon"

    Thank you!!!

    How soon is soon lol?

    • Not sure why we are laughing out loud.(lots of Love)..but it will be as soon as referees accept the stuff maybe next week…maybe next year. The publication process has become so tiresome and frustrating.

    • The paper should be open access, so once the proffs are done I will say more once every one can read the content

    • lol = because I am impatient. I laugh every time I follow a "thank you" with a request for something more. I consider it a recognition that I am demanding.

  • What would you suggest may be the cause of relapses in patients 6-8 months post Alemtuzumab? Could it somehow be related to B-cell hyperproliferation?

    • I would assume there was disease activity but this popoulation could be gold dust because there should be few lymphocytes and the disease causing cells should show themsleves. I know this has been looked at in bog standard T and B cell typing and there has been nothing found but they have not looked in the right way.However although people are tested monthly their lymphocytes are thrown away, they should be banked!

      Maybe, I am waiting to see if we can get access to thius data

    • So would treatment with Ocrelizamub be preferable rather than a second and possibly subsequent courses of Alemtuzumab?

  • Wow!!! This is very good !!
    In the rush of work I couldn't read the blog in the last few days, but when I come to the blog I come across this excellent news! I had already talked to a friend oncologist and she said that if the EM-EBV-autoimmunity hypothesis was correct, Alemtuzumabe would be targeting the infected B cells and the secret to success would be to find out how to avoid the autoimmunity caused by Alemtuzumabe…

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