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
“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