Sunday, 14 May 2017

Nothing like a good idea seemingly exploding. Reconstitution after HSCT.

Karnell FG, Lin D, Motley S, Duhen T, Lim N, Campbell DJ, Turka LA, Maecker HT, Harris KM.Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin Exp Immunol. 2017. doi: 10.1111/cei.12985.

Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. In a phase II clinical trial, high-dose immunosuppressive therapy combined with autologous CD34+ hematopoietic stem cell transplant resulted in 69.2% of subjects remaining disease-free without evidence of relapse, loss of neurological function or new MRI lesions through year 5 post-treatment. A combination of CyTOF mass cytometry and multi-parameter flow cytometry was used to explore the reconstitution kinetics of immune cell subsets in the periphery post HSCT and the impact of treatment on the phenotype of circulating T cells in this study population. Repopulation of immune cell subsets progressed similarly for all patients studied 2 years post therapy, regardless of clinical outcome. At month 2, monocytes and NK cells were proportionally more abundant, while CD4 T cells and B cells were reduced, relative to baseline. In contrast to the changes observed at earlier time points in the T cell compartment, B cells were proportionally more abundant and expansion in the proportion of naïve B cells was observed 1 and 2 years post therapy. Within the T cell compartment, the proportion of effector memory and late effector subsets of CD4 and CD8 T cells was increased, together with transient increases in proportions of CD45RA- Tregs, and Th1 cells, and a decrease in Th17.1 cells. While none of the treatment effects studied correlated with clinical outcome, patients that remained healthy throughout the 5-year study had significantly higher absolute numbers of memory CD4 and CD8 T cells in the periphery prior to stem cell transplantation


HSCT immune replacement is the ultimate replacement therapy. This study suggests on reading the abstract that my hope of finding something in the B cell compartment may not occur. 

But it does tell us something about how immune populations reappear after depletion. 

(1). It says that when you deplete T cells it is the memory cell population that expands up the quickest and indeed that is what was seen after treatment with alemtuzumab and also CD4 depleting antibody. It is laos seen in the animals.

(2). In contrast, B cell repopulation is seen with a a surge of immature that convert into naive/mature cells and this is seen following alemtuzumab and rituximab treatment and presumably ocrelizumab treat when the B cell subset reconstitution data in MS, is eventually shown.  

Remember these two facts when I talk about this in the not too distant future.  

This does not tell us if disease is going to re-activate and indeed is going to create the smoke screen, when we look for which cell types are going to trigger relapse. 

There is a suggestion of increases in T regs (yeah), based on proportions, just like that reported after alemtuzumab and a decrease in Th17 so dogma can be preserved.  We say this with the DMF study last week and when you look at absolute numbers you get a different answer,

However, for all the phenotpying they could not see anything that related to disease activity and the people that remained healthier had more memory T cells prior to stem cell therapy. So is it Protective Autoimmunity?

This blanket look-see without any thought what is important is great, but it means you "can't see the woods for the trees". 

Earlier this year we have pinned out mast on the memory B cell and one would hope that if you look at this population there may be some change to correlate with disease activity.

Free read the paper CLICK

On reading the abstract I thought, bang there goes the Idea of B memory cell function relating to disease activity. 

However, the study only examined 23 pwMS and of them only 7/23 relapsed, so we are looking for a wood made up of a few twigs, so are we going to find the wood in a thicket? 

However, in this study they did not even look for the right wood as they only reported examination of T memory cell function. 

So the B memory cell idea is not dead....yet. 

But it shows us where the science interest is, and that is Th17, T reg and T cells, T cells, T cells. 

I'll write to the authors so they can put me out of my misery with knowing what happens to B memory cells. 

However, we know from rituximab studies that you can relapse and have no B cells in the blood so it is not a dead idea yet. Likewise if EBV is in the frame the memory cells will repopulate like crazy.

Importantly the main action may not be in the blood, but if new lesions are forming surely somethings happens.

11 comments:

  1. In this this study (Tbi and atg
    )https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/
    They say :Memory B cell
    counts recovered more slowly than naïve B cell counts. This may be because naïve B cells only
    differentiated into memory B cells after encountering their cognate antigens
    Could be that hsct works until they recover fully?

    ReplyDelete
    Replies
    1. I suspect that disease can occur before they get up to full recovery.

      Delete
  2. So why are people 17 years free from ms after hsct?
    Could it be that they dont ever recover in those cases?
    Thanks for your answer

    ReplyDelete
    Replies
    1. I don't know, the idea I work to is that they pathogenic cells repopulate into an environment where they are effectively regulated as the pathogenic ones repopulate slower than the regulation

      Delete
    2. So the "Immune system reseting" idea holds are all?

      "It has been demonstrated that auto-reactive T cells recognizing
      oligodendrocyte epitopes are present in healthy individuals as well as in MS
      patients.35 From this we can conclude that the ability to recognize self is not
      enough to generate an autoimmune response in this context
      Joachim Burman
      Could hsct return the patient to a pre-ms state?

      Delete
    3. Could hsct return the patient to a pre-ms state?

      No...it is not going to turn back the clock. Damage done is done, although it will allow the repair process.

      In terms of the immune systme it may indeed turn the clock back.

      Delete
    4. Thank for replying
      Thats what i was saying in terms of the immune system
      Could it be that the immune system is prone to covert again to ms later on ? As in the prestages of ms onset?
      Thanks Luis

      Delete
    5. This study (24 pwMS) showed no new disease activity post aggressive (near complete immunoablation) HSCT. 1 pwMS died of the procedure.
      http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30169-6/abstract
      There is a risk though (about 10%) of the development of other secondary autoimmunities post HSCT.

      Delete
    6. I know this one very well and also this http://www.neurology.org/content/early/2017/02/01/WNL.0000000000003660.short?rss=1
      Halt-ms 5 years results in february this year
      They are identical in the nº of patients and outcomes
      As with the most eficacy frugs like alemtuzumab there is increased risk of cancer and secondary autoimmunities
      Thanks again for replying
      I thought you are against Hsct for Ms?
      Leave you with this presentation of Dr James Bowen a great speaker and co director of the Halt-Ms Study
      https://www.youtube.com/watch?v=5yJ8XPvgSgY
      Luis

      Delete
    7. Not sure why you say I'm against hsct. If you accept ms drugs work then replacing the immune system must also. However it is not infallible like all ms treatments. Question is do you need to take the nuclear option against other options

      Delete
    8. Lolllll....Well put...
      I like the one:
      Ms is like a fire in some cases burns stong and fast
      In others weak and long
      In any case you have to stop it as soon as possible
      Thanks for replying
      Luis

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.