Tuesday, 28 April 2015

Research Day 2015 Dr Saxton and Excerise

Today we have a guest speaker-Dr. John Saxton that was asked to attend to take about exercise

Blocking microglial could this affect progression

Savarin C, Hinton DR, Valentin-Torres A, Chen Z, Trapp BD, Bergmann CC, Stohlman SA.Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis.J Neuroinflammation. 2015;12(1):79. [Epub ahead of print
BACKGROUND:Therapeutic modalities effective in patients with progressive forms of multiple sclerosis (MS) are limited. In a murine model of progressive MS, the sustained disability during the chronic phase of experimental autoimmune encephalomyelitis (EAE) correlated with elevated expression of interleukin (IL)-6, a cytokine with pleiotropic functions and therapeutic target for non-central nervous system (CNS) autoimmune disease. Sustained IL-6 expression in astrocytes restricted to areas of demyelination suggested that IL-6 plays a major role in disease progression during chronic EAE.
METHODS:A progressive form of EAE was induced using transgenic mice expressing a dominant negative interferon-γ (IFN-γ) receptor alpha chain under control of human glial fibrillary acidic protein (GFAP) promoter (GFAPγR1Δ mice). The role of IL-6 in regulating progressive CNS autoimmunity was assessed by treating GFAPγR1Δ mice with anti-IL-6 neutralizing antibody during chronic EAE.
RESULTS:IL-6 neutralization restricted disease progression and decreased disability, myelin loss, and axonal damage without affecting astrogliosis. IL-6 blockade reduced CNS inflammation by limiting inflammatory cell proliferation; however, the relative frequencies of CNS leukocyte infiltrates, including the Th1, Th17, and Treg CD4 T cell subsets, were not altered. IL-6 blockade rather limited the activation and proliferation of microglia, which correlated with higher expression of Galectin-1, a regulator of microglia activation expressed by astrocytes.
CONCLUSIONS:These data demonstrate that astrocyte-derived IL-6 is a key mediator of progressive disease and support IL-6 blockade as a viable intervention strategy to combat progressive MS


Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory cytokine. IL-6 is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. IL-6 also plays a role in fighting infection,. IL-6 role as an anti-inflammatory cytokine. IL-6 is an important mediator of fever and of the acute phase response. It is capable of crossing the blood-brain barrier and changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These are present on the cell surface and intracellular compartments and induce intracellular signalling cascades that give rise to inflammatory cytokine production. IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.

IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing componentgp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor (LIF), ciliary neurotropic factor,oncostatin M, IL-11 and cardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs).

In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination. It may be able to inhibit microglial function. Maybe this could be tested to see if it affected progression.However would this be associated with a lot of side effects because IL-6 can do so many different things.

Whats in Name 28th

This week it is MS awareness week in the United Kingdom

Scientists and Neuros and health care professionals write papers every day and you are increasingly getting to see them with open source information. It is interesting how they refer to you in these papers and grants. Maybe it is time you said what you prefer. 

What's In Name?

We have asked this before and now I am asking this again. Why? 

      We get trolls that try to damage our professional reputations  
and in doing this hasten the end of this Blog.

So I would ask you to consider helping us and
consider signing up to the MS Register 
to help me respond to the Trolls
&
We are seeking independent assistance to get a bigger sample size
to address journal editors concerns

The MS Register is a ground-breaking study designed to increase our understanding of living with MS in the UK.

Are you over 18, living in the UK , with a confirmed diagnosis of Multiple Sclerosis?  Then you need to take part in this ground breaking study (Click here) 

Once you have completed the registration form you will find a series of questionnaires please complete them, notably 

What's in a Name.

For your reassurance, The MS Register has gained official approval from the National Research Ethics Service Committee South West - Central Bristol. To gain this approval, Swansea University College of Medicine was required to go through a thorough audit of information management practices.

If you opt-out from the MS Register, your details will be deleted
If, at any point, you decide you would rather not continue to take part in the MS Register, just let the MS Register know. Although the information you have given them through our online questionnaires or clinical study will remain in their database, they will delete your name and address and will have no way of linking this information to you.

Disclaimer By completing our survey "What's in a Name" you are consenting to the data you provide being analysed by the MS register and possibly Professors Giovannoni and Baker and their collaborators. Results of these surveys may be submitted for publication but will be anonymous.


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Also one of the biggest things that came from Pharma interest in MS, which makes a positive impact to people with MS, is the MS Specialist Nurse.

The MS Trust is running a campaign to ensure you all get access to an MS Nurse..Join the campaign.....I have....and sign up! 



It costs you nothing except about a minute of your time.



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Live in Australia sign up to their Registry  (Click here)

Live in the USA sign up to their Registry (Click here)
Sorry you can't do our survey, but sign up to 
help researchers in your Country

My take on AAN 2015

Selected posters from AAN 2015


The White House - it really is white! Dulux paint match anyone?


Pathology i.e. anything about the disease itself


1. Immune response to EBV (Epstein Barr virus) in MS - poster by Murali Ramanathan and colleagues (State University of New York)


EBV-infected B cells are thought to induce meningeal (the region covering the brain) inflammation, which may contribute to cortical damage (the cortex is the outer surface of the brain, conversely the inner portion of the brain is made up of white matter tracts, excluding the deep grey matter).

They performed brain scans and measured the subjects antibody levels to EBV; specifically to its viral capsid antigen (VCA) and nuclear antigen-1 (EBNA-1). 

In MS patients, high anti-EBV VCA (i.e. the higher quartile group) was associated with increased T2 lesion volume, T1 lesion number and volume, and decreased normalized grey matter volume (NGMV) and normalized cortical volume (NCV) - see table below. In RRMS alone, anti-EBNA-1 highest quartile group had increased T1 lesion number, and decreased NGMV and NCV.



Looking at the p-values the greatest are those associated with focal pathology (T1 and T2), hinting at more severe white matter pathology. But this may be due to the relative difficulty of performing grey matter and cortical volume measures leading to greater errors. Nonetheless, there does appear to be advanced cortical pathology, and chronic T1 black holes in high EBV titre group. 

Interesting work, and a good sample size (539 MS patients). We need to see whether there are regional differences by country.


Disease monitoring i.e. investigations


1. MRI brain atrophy - poster by MS-STAT investigators reporting on MRI brain volume analysis in SPMS


MS-STAT was a randomized-placebo controlled study of 80mg simvastatin vs. placebo. The study demonstrated a 43% annualized reduction in whole brain atrophy rate in simvastatin vs placebo.

They found that higher rates of brain atrophy was associated with worsening disability in EDSS (expanded disability scoring system), 25 foot walk, 9 hole peg test speed, calculation ability (PASAT scores) and worsening psychological scores (see figure below).

Measuring brain volumes and atrophy is proposed as a part of NEDA-4 (no evidence of disease activity), therapies able to prevent or stabilize brain volume loss are currently being investigated in SPMS.


Conflict of interests - several in our group.

2. Body fluid biomarkers (cerebrospinal fluid Fetuin A, S100B, and glial fibrillary acidic protein - GFAP) - poster by Ayse Altintas and colleagues (University of Isanbul and Ulm)


Fetuin A is a marker of inflammatory activity, S100B of astrocytic activity and GFAP of astrogliosis.

Not surprisingly, CSF-GFAP and S100B was associated with severe disease independent of disease subtype (see table below). Measuring the two in addition to neurofilaments may prove to be useful prognotically in progressive MS.



Washington monument during the day and at night from the roof of W hotel.

The treatments i.e. drugs


1. ALEMTUZUMAB (aka Campath-1H, Lemtrada) - poster by CARE-MS II investigators


Alemtuzumab is a humanized anti-CD52 (a protein present in mature lymphocytes) monoclonal antibody, which targets these lymphocytes for destruction. It was the most talked about MS therapy at the conference with several posters looking at various aspects of the drug. I have picked below the poster assessing its efficacy on clinical disability.

In the CARE-MS II study in active RRMS alemtuzumab was superior IFN beta-1a (Figure 1 showing a better EDSS score in alemtuzumab at mth 24 - blue dots). All were invited to partake in the extension study but only the data from those allocated to alemtuzumab in the core study is presented. Participants received repeated doses of alemtuzumab only if they relapsed or had breakthrough MRI activity - 68% didn't require re-dosing at 4 years.

43.5% (Figure 2 - last column) improved whilst 27.8% remained stable in their EDSS scores from the start of the study to year 4 if they only received the initial two infusions an year apart. But (and this is a big one) 28.7% had an increase in their EDSS score. My take on this is that induction alone is not sufficient and adjunctive therapies may be needed in the interim; whether it be neuroprotective therapies or other immunomodulatory therapies.


















In terms of side effects, thyroid problems are the commonest - roughly just over a third of patients experiencing it. The occurrence of thyroid related side effects peaked at year three from the initial infusions before declining (see figure below).



Conflict of interests - several from our group.

2. Effectiveness of switching from natalizumab to rituximab over fingolimod or dimethyl fumarate - poster by Enrique Alvarez and colleagues (University of Colorado)


We know that stopping natalizumab (for e.g. because of JCV positivity) can result in rebound or return of disease activity. The group wanted to test the efficacy of switching therapies, such as rituximab, fingolimod and dimethyl fumarate. Thier wash out period from natalizumab was < or equal to 6 months (on average 0-1 months). 

They found that irrespective of switching therapies resulted in little disease activity (1.5% in retuximab, 4.0% in dimethyl fumarate, 1.8% in fingolimod). In 12 months of switching therapies, however, rituximab fewer enhancing lesions and discontinuation of treatment.

Interesting study, but a huge note of caution; the patients were not randomized (i.e. the switch therapies were not randomly assigned to each patient giving rise to bias in selection), nor are the sample sizes of sufficient number to generalize the findings to anyone around the world. More work is evidently needed in this area. Although promising, I will question the safety of switching JCV+ patients to another highly active infusion therapy - and data is specifically needed in this group (is this ethical to do such a study?).


3. Safety and tolerability of oral RPC1063 in RRMS - poster by RADIANCE trial investigators


RPC1063 is a new version of fingolimod and is a sphingosine 1-phosphate (S1P) 1,5 receptor modulator. RADIANCE is an ongoing clinical trial the group presented the Phase 2 portion of the study.

Low post-dose heart rate in fingolimod is an issue, however, with this latest version the drop in heart rate was modest. During the first 6 hours post dose reduction in heart rate was <2 beats per min from the starting heart rate. Neither was there any clinically significant conduction abnormalities observed. This version may prove to be the best in its class, although we will know more once the study completes.

RPC1063 is a mouthful, I wonder what name will be assigned!

4. Daclizumab HYP versus IFN beta-1a - poster by DECIDE study group investigators


Daclizumab is a monoclonal antibody which modulate IL-2 signaling by binding the alpha subunit (CD25) of the IL-2 receptor (IL-2R) of T cells thereby inhibiting high-affinity IL-2R signaling with immunomodulatory effects.

Compared to IFN-beta-1a lowered annualized relapse rates by 45%, reduced the proportion of patients who relapsed by 41%, and reduced the number of T2 lesions by 54% at week 96. 

This is a treatment for RRMS as you can see by the figure below greater disease duration (> or equal to 10years) and high EDSS scores (> or equal to 3.5) do not favor dacalizumab treatment.

 

I was slightly disappointed with this study as I thought the data will be better than alemtuzumab but not so. However, head to head comparisons need to be performed and route of administration needs to be factored; as dacalizumab is subcutaneous delivery and may be more suitable for home administration if your nearest MS center is on Mars for instance!

Conflict of interests - several in our group.


Abraham Lincoln (top) and part of his second inaugral address (bottom)


General 


1. Stress burden in caregivers looking after RRMS patients - poster by Jose Meca-Lallana and colleagues (from Spain)


Caregiver burden in those looking after MS patients is multi-factorial, dependent on physical, psychological, emotional, social and financial factors. In this study they found that EDSS score (odds ratio 1.6), time as a caregiver (odds ratio 1.1) and number of medications administered were associated with increased burden. Not surprisingly, they also found the availability of new DMTs has changed the perception of the disease by carers and patients in RRMS (see below).


The Book (1979-85), Anselm Kiefer in the Hirshhorn gallery. The unreadable tome juxtaposed against a desolate landscape conveys as sense of melancholy, suggesting the ways in which cultures create and disseminate destructive ideologies through the written word.