Friday, 23 February 2018

HSCT and T cells and MS and memory B cells

What cells are important to target in HSCT?


Harris KM, Lu T, Lim N, Turka LA. Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity. Front Immunol. 2018 ;9:100. doi: 10.3389/fimmu.2018.00100. eCollection 2018.
Autoimmunity represents a broad category of diseases that involve a variety of organ targets and distinct autoantigens. For patients with autoimmune diseases who fail to respond to approved disease-modifying treatments, autologous hematopoietic stem cell transplantation (AHSCT) after high-dose immunosuppressive therapy provides an alternative strategy. 

Although more than 100 studies have been published on AHSCT efficacy in autoimmunity, the mechanisms that confer long-term disease remission as opposed to continued deterioration or disease reactivation remain to be determined. 

Hasn't read our papers...its the B cell :-)

In a phase II clinical trial, high-dose immunosuppressive therapy combined with autologous CD34+ haematopoietic stem cell transplant in treatment-resistant, relapsing-remitting multiple sclerosis (RRMS) resulted in 69.2% of participants achieving long-term remission through 60 months follow-up. 

HSCT is a pretty good DMT :-)

Flow cytometry data from the 24 transplanted participants in the high-dose immunosuppression and autologous stem cell transplantation for poor prognosis multiple sclerosis (HALT-MS) trial are presented to illustrate immune reconstitution out to 36 months in patients with aggressive RRMS treated with AHSCT and to highlight experimental challenges inherent in identifying biomarkers for relapse and long-term remission through 60 months follow-up. AHSCT induced changes in numbers of CD4 T cells and in the composition of CD4 and CD8 T cells that persisted through 36 months in participants who maintained disease remission through 60 months.

So if you think MS is a T cell problem you look at T cell numbers and what do you find?


However, changes in T cell phenotypes studied were unable to clearly discriminate durable remission from disease reactivation after AHSCT.

Yep......nothing. Is this surprising?

When we suggested memory B cells may be important

An Editor of a prestigious Neurology journal said "

"the existing work lacks sufficient evidence that the effect is actually mediated via an impact on memory B cells"

What a m****t....because how do you prove that any cell type is the cause in human disease? You can't! 

Furthermore you should not try to prove anything you should try and disprove the idea...This is Popperian Science. A theory in the empirical sciences can never be proven, but it can be falsified.

Where is the proof that MS is caused by T cells?

T cells are depleted by the HSCT but I suspect so are the memory B cells, However it is clear that T cell numbers do not correlate with disease activity. 

This is the case with alemtuzumab

Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J. Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.
Neurology. 2014; 82(24):2158-64.


and cladribine
Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K.Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017; 4(4):e360.

Will it correlate with B cell number, maybe...maybe not  but if we don't look we will never know.

But in this study we have remssion of MS associated with low memory B cell numbers especially compared to neuromyelitis optica disease of spinal cord and optic nervve.

Ip PP, Chung CY, Chang CC, Lee YF, Wang HM, Lian IB, Fann CS, Yang CC, Liao F. Differentiation of remitting neuromyelitis optica spectrum disorders from multiple sclerosis by integrating parameters from serum proteins and lymphocyte subsets. J Neuroimmunol. 2018 Feb 8. pii: S0165-5728(17)30498-8.


Differential diagnosis for neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) is always doubtful. To differentiate these diseases, we studied the immune status in the blood of patients with MS (n = 45) or NMOSD (n = 23) at remission phase. Remitting NMOSD patients had increased levels of CXCL13 and memory B cells, while remitting MS patients had elevated levels of galectin-9 and Th1 cells. A diagnostic model with these four variables is built to distinguish remitting NMOSD from MS with a sensitivity of 91.30%. Our diagnostic model may help to improve the differentiation of remitting NMOSD from MS.


So in remitting MS there are fewer memory B cells.. That's fine but it is all based on percentages and not actual numbers so they show a good correlation between the level of naive B cells and memory B cells, which is not surprising becuase as one goes up the other goes down. this is why is is so important to work from absolute numbers of cells.

However in this study the people with MS are on treatment and we can see that there are 14.5% memory B cells following interferon treatment and  6% after fingolimod consistent with fingolimod being a more effective DMT and with natalizumab , memory B cells are trapped in the blood and there is 34% memory B cells.

This is what we have reported previously so supporting our concepts and previous studies, but if we look at T cells with interferon there is 7% with interferon and 27% with fingolimod, which does not fit with fingolimod being more effective.

Data are given as median (range); #Kruskal Wallis test.
Types of treatment
IFNβ-1aFingolimodNatalizumabOthersNone
Variables(n = 26)(n = 9)(n = 3)(n = 4)(n = 3)p-Value#
(b) MS patients
CXCL10459 (37.33–3186.70)175 (81.75–565.71)176 (165.50–405.60)166 (66.86–266.79)131 (58.45–327.20)0.0632
CXCL1347.02 (3.50–284.38)3.50 (3.50–29.28)49.44 (11.09–245.06)29.47 (11.97–295.53)20.50 (14.84–47.53)0.0089⁎⁎
Galectin-91559 (291–2501)747 (528–1017)1065 (1057–1441)864 (598–1252)714 (706–1584)0.0064⁎⁎
Th1 CD4+ T cells6.94 (0.98–63.50)28.60 (8.47–87.90)20.80 (15.80–26.30)3.42 (2.15–9.11)10.30 (5.52–13.20)0.0003⁎⁎⁎
Naïve B cells78.06 (22.27–91.89)73.78 (51.03–94.70)56.16 (18.45–60.40)70.65 (65.18–70.90)54.39 (51.03–83.19)0.0551
Memory B cells14.45 (4.53–70.22)6.00 (0–33.86)33.51 (20.06–78.74)23.89 (21.02–28.00)18.11 (11.74–38.65)0.0162
Data are given as median (range); #Kruskal Wallis test; p < 0.05; ⁎⁎p < 0.01; ⁎⁎⁎p < 0.001.

3 comments:

  1. "..MS are on treatment and we can see that there are 14.5% memory B cells following interferon treatment and 6% after fingolimod.."

    What do you think Rituximab memory B cell percentage would be..?

    ReplyDelete
  2. lol. your frustration at your t cell friends makes me think of the frustration people with ms enquiring about hsct experience when their neuros give them advice on hsct :)

    ReplyDelete

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