Saturday, 25 March 2017

MS lymphocytes making new myelin

El Behi M, Sanson C, Bachelin C, Guillot-Noël L, Fransson J, Stankoff B, Maillart E, Sarrazin N, Guillemot V, Abdi H, Cournu-Rebeix I, Fontaine B, Zujovic V.
Brain. 2017. doi: 10.1093/brain/awx008. [Epub ahead of print]

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. 

Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. 

Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. 

Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. 

Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.

Last week we had the story that Treg cells produced a molecule that promoted remyelination and this week we have something similar but they take human cells and inject them into a nude mouse.

A nude mouse is a mutant mouse that does not make hair, but they also do not make T cells and so they can't reject human cells that are transplanted into the mouse. They injected a toxin to make demyelinated lesion as the toxin kills oligodendrocytes.

They then inject human cells, which they have activated,into the mice and find that they promote repair. As the mice were not genetically engineered e.g. to be MHC compatible, the T cells would not be able to talk to the lymphocytes. They go a test bleed from the eye by putting a needle into the retro-orbital sinus, which was banned (as their are alternatives) in the UK about 25 years ago, to check the cells are still present. They find there is variability in the repair potential, They found that MS blood cells demonstrate that multiple sclerosis lymphocytes did not interfere with OPC recruitment, but impeded OPC differentiation. This had an effect of via microglial cells and when they looked at 72 secreted molecule they found differences in three IL-7 and IL-20 which are immune growth factors and CCL-19 which is a protein that attracts cells called a chemokine. The latter was lower from people with MS. 
Taking advantage of our innovative in vivo model to study the role of human lymphocytes in remyelination, we demonstrated a strong implication of adaptive immune cells in this repair process. In particular, multiple sclerosis patient lymphocytes induce detrimental environment for the repair process notably by directing MIGs toward a pro-inflammatory M1 phenotype. Strikingly, the molecular cues needed for a successful remyelination were different when considering multiple sclerosis patient and healthy donor lymphocytes

Friday, 24 March 2017

#PoliticalSpeak: impact or lack of impact

Why has academia become so bureaucratic? #PoliticalSpeak #MSBlog

Life as an academic is becoming increasingly complicated and frustrating; I spend an extraordinary amount of time doing administration. We have been asked to start preparing for the next REF, which is likely to be in 2020, and need your help. 

In the UK academic institutions are assessed every 6-7 years as part of the Research Excellence Framework exercise or REF. As part of this assessment we have to provide 'impact case studies' demonstrating the impact of our research on wider society. Impact is defined as ‘an effect on, change or benefit to the economy, society, culture, public policy or services, health, the environment or quality of life, beyond academia’.

We had an informal discussion yesterday about what academic activities we are engaged in have impact and how can we show impact. If we have to submit an impact statement next REF we will need to be able to demonstrate how we are having impact with the relevant metrics, etc. As you are quite close to our activities you could help us prioritise our efforts so that we can focus on the academic activities that are most likely to succeed. This exercise will also help focus our minds as a group. Thank you. 

CoI: multiple

More on B cells.We don't all have the same ideas. Who is right?

We don't normally report on reviews. But we have a couple of recent ones

Nguyen AL, Gresle M, Marshall T, Butzkueven H, Field J. "Monoclonal antibodies in the treatment of MS: emergence of B-cell targeted therapies". Br J Pharmacol. 2017 Mar 20. doi: 10.1111/bph.13780. [Epub ahead of print]

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, and one of the most common causes of disability in young adults. Over the last decade, new disease modifying therapies have rapidly emerged, including monoclonal antibodies (mAbs) that have provided highly targeted therapies with superior efficacy compared to platform therapies. In particular, monoclonal antibodies directed against CD20-positive B cells have shown remarkable results in recent clinical trials, and renewed interest in the mechanism of B-cell depleting therapies to ameliorate relapse activity and progression in MS. In this manuscript, we will review the mechanisms of action and clinical evidence of approved and emerging mAbs, with a focus on B-cell targeted therapies

We did the same but came to very different conclusion.
Here it is all to do with B cell regulatory function rather 
than B memory function.

If you work in percentages if one goes down (Memory B cell subsets) the others (Regulatory B cells) must go up.

However in some cases because we have tried to work with absolute numbers we know that B memory cells go down

We have recently published 
our first part of the original series of papers written 
just before Christmas.
The last part of the originally submitted studies 
actually surfaced first

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
EBioMedicine. 2017 Feb;16:41-50. doi: 10.1016/j.ebiom.2017.01.042

This has gained some Interest on the Blog as it becomes evident that this subset of Bcells is infected by Epstein Barr Virus.

Maybe there are alternative explanations to the view that B cells help T cells do it all.

Following dogma can lead us down a garden path, as we will see as the next part of the equation eventually surfaces.

However, this thought does not even occur on some people's radar
So here is a standard view

Ocrelizumab in multiple sclerosis: markers and mechanisms.
Hohlfeld R, Meinl E. Lancet Neurol. 2017;16(4):259-261.

They say

"Anti-CD20 therapy acutely depletes CD20+ cells in the periphery, but only causes a delayed and modest decline of circulating antibodies.CSF studies with rituximab revealed decreased T-cell and B-cell counts, whereas intrathecal IgG production was relatively spared. For these reasons, depletion of pathogenic antibodies might not be the dominant mechanism of action of ocrelizumab in multiple sclerosis, although this cannot be totally excluded". 

"Overall, it seems plausible that anti-CD20 therapy partly acts by eliminating the potent antigen-presenting function of B cells, a view supported by animal experiments. Furthermore, B cells produce many pro-inflammatory and anti-inflammatory cytokines. Profound B-cell depletion might therefore lead to changes in the cytokine network, dampening pathogenic T-cell responses and thereby contributing to the beneficial effect of anti-CD20 therapy in multiple sclerosis".

"Lastly, it should be noted that anti-CD20 therapy is not entirely specific for B cells, as it also depletes CD20+ T cells, which are about 5% of blood T cells".

Whilst our review accommodates all these views, it gives an opinion and then it puts the focus in a very different direction. As memory B cells are not really mentioned. However, again we see that animal studies again tell us how MS drugs work. 

Although I am aware that the animal studies support such a mechanism, I personally think the data from treatment of animals with anti-CD20 is weak. 

Should we do a critique of the animal data? 

If the animal data is on shaky ground, where does it leave the hypothesis?

Do Mice Have Paws? What have they got?

We have been requesting access to data from pharma relating to B cells and disease activity.  As we told you, we got kicked back by some of the Companies, 

This prompted ProfG to start a petition to ask 

Ely Lilly to release their anti-B cell in MS trial data 
(Click here to sign)

One of the bloggers to say the least was very angry at this and wrote "MD. I've a few old uni friends work for pharma (lovely people) but I've taken this a bit personally. I sincerely hope you get your paws (do mice have paws?) on this eventually. Keep writing the papers! And thanks for sharing them with us, ignore any criticisms I love your posts - they usually make me laugh too" 

Do mice have paws?

The answer is yes, and we already have or paws on something.

Why have we started writing about B cells?  

Check out the acknowledgement in our B cell paper

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis :-)

FYI. We have moved up the command chain to by-pass Roadblock#1. 

It was poetry world day this week so

Whilst mice have paws ferrets have locking jaws:-)

Thursday, 23 March 2017

Natural Killer cells and MS

Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia.Caruana P, Lemmert K, Ribbons K, Lea R, Lechner-Scott J. Mult Scler. 2016:1352458516679267. doi: 10.1177/1352458516679267

To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity.

METHODS: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to 'No Evidence of Disease Activity' (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression.

RESULTS: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment ( p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects ( p < 0.05).

CONCLUSION: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

So a suggestion that NKbright cells that are expanded by daclizumab in this study they suggest high levels are associated with stable disease...Is this a sign that its not B cells?