Friday, 23 February 2018

HSCT and T cells and MS and memory B cells

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.

TeamG in the News...used for Crowd funding

ProfG and DrK were in the media yesterday as they launched their #Thinkhand campaign.

Yep this is old news on the blogsphere, but the Evening Standard (Local London Newspaper) picked up the story and pulled a fast one


Thursday, 22 February 2018

Putting the CART before the horse: could CAR-T cells be a last-resort therapy in MS to rival HSCT?

First off, apologies my long winter hibernation from the blog. As you may have gathered (if anyone is paying close attention to my blogging habits) I'm no longer full-time at BartsMS, and have been working in mental health down the road at Mile End. There are loads of interesting things to say about the overlap between MS and mental health, lots of which have been discussed before on the blog. 

#ThinkHand: Today is MS Hand Awareness Day

We are hosting our #ThinkHand Awareness event tonight. The good news is that Shift.ms will be there to help promote the campaign. The following are some YouTube clips, from their reporters, explaining the campaign and how you can help. 

Thank you Shift.ms for helping and spreading hope for the million-plus people who have MS and are using a wheelchair.




Wednesday, 21 February 2018

Barts Health CSF Neurofilament light chain (NfL) request


As promised, any clinician based in the UK can request the neurofilament light chain for Multiple Sclerosis. Your hospital laboratory would need to discuss the transfer of you CSF sample to our lab:

Dr David Holden
Centre for Neuroscience and Trauma,
Queen Mary University of London,
4 Newark St
London
E1 4AT

Email: d.w.holden@qmul.ac.uk

A sample request form is below:



The final report that you receive will look something like this:



If there are particular questions with regard to sample volume, storage and transport Dr Holden will be able to answer them.

Vitamin C for myelination

What has vitamin C got to do with MS?


Our Prime Minister has the decency to send her apologies

We are hosting our #ThinkHand awareness event tomorrow night. We were hoping to get Theresa May to attend and endorse the event. At least she responded. JK Rowling didn't even acknowledge our invitation. Very poor form? 




Tuesday, 20 February 2018

CSF neurofilament light chain and OCB predict conversion to MS in RIS

CSF neurofilaments are ready for prime time. Do you agree? Wouldn't you as someone with MS not want to know what their CSF NFL levels were? 


Inflammation and nerve damage occur before you even know you have MS

I didn't realise that NDG had done this but here are my thoughts...

Monday, 19 February 2018

Here comes #ChariotMS. Or does it?

Is the #ChariotMS study worth funding? Is upper limb function worth saving in people with more advanced MS?



The objectives of our #ThinkHand awareness event, which we are hosting this Thursday night, is to celebrate hand function in people with MS and to promote #ChariotMS to the wider community.