lessons for translation: srma in understanding the ... disease 0.464 0.066 0.470 0.530 0.464...
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Emily Sena, Gillian Currie, Hanna Vesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca, Zsannet Bahor, Jing Liao,
Theo Hirst, Kim Wever, Hugo Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru, Stelios Serghiou, AaronMcLean, Catherine Dick, Tracey Woodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu, Sarah MaCann, GillianMead, Joanna Wardlaw, Rustam Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian Whittle, Andrew Rice,
Rosie Moreland, Nathalie Percie du Sert, Paul Garner, Lauralyn McIntyre, Gregers Wegener, Lindsay Thomson, DavidHowells, Ana Antonic, Tori O’Collins, Uli Dirnagl, H Bart van der Worp, Philip Bath, Mharie McRae, Stuart Allan, Ian
Marshall, Xenios Mildonis, Konstantinos Tsilidis, Orestis Panagiotou, John Ioannidis, Peter Batchelor, David Howells,Sanne Jansen of Lorkeers, Geoff Donnan, Peter Sandercock, Emily Sena, Gillian Currie, Hanna Vesterinen, KierenEgan, Nicki Sherratt, Cristina Fonseca, Zsannet Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo Pedder, Katerina
Kyriacopoulou, Julija Baginskaite, Ye Ru, Stelios Serghiou, Aaron McLean, Catherine Dick, Tracey Woodruff, PatriceSutton, Andrew Thomson, Aparna Polturu, Sarah MaCann, Gillian Mead, Joanna Wardlaw, Rustam Salman, Joseph
Frantzias, Robin Grant, Paul Brennan, Ian Whittle, Andrew Rice, Rosie Moreland, Nathalie Percie du Sert, Paul Garner,Lauralyn McIntyre, Gregers Wegener, Lindsay Thomson, David Howells, Ana Antonic, Tori O’Collins, Uli Dirnagl, H Bartvan der Worp, Philip Bath, Mharie McRae, Stuart Allan, Ian Marshall, Xenios Mildonis, Konstantinos Tsilidis, Orestis
Panagiotou, John Ioannidis, Peter Batchelor, David Howells, Sanne Jansen of Lorkeers, Geoff Donnan, PeterSandercock, Emily Sena, Gillian Currie, Hanna Vesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca, Zsannet
Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru, SteliosSerghiou, Aaron McLean, Catherine Dick, Tracey Woodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu, SarahMaCann, Gillian Mead, Joanna Wardlaw, Rustam Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian Whittle,
Andrew Rice, Rosie Moreland, Nathalie Percie du Sert, Paul Garner, Lauralyn McIntyre, Gregers Wegener, LindsayThomson, David Howells, Ana Antonic, Tori O’Collins, Uli Dirnagl, H Bart van der Worp, Philip Bath, Mharie McRae,
Stuart Allan, Ian Marshall, Xenios Mildonis, Konstantinos Tsilidis, Orestis Panagiotou, John Ioannidis, Peter Batchelor,David Howells, Sanne Jansen of Lorkeers, Geoff Donnan, Peter Sandercock, Emily Sena, Gillian Currie, HannaVesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca, Zsannet Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo
Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru, Stelios Serghiou, Aaron McLean, Catherine Dick, TraceyWoodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu, Sarah MaCann, Gillian Mead, Joanna Wardlaw, Rustam
Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian Whittle, Andrew Rice, Rosie Moreland, Nathalie Percie duSert, Paul Garner, Lauralyn McIntyre, Gregers Wegener, Lindsay Thomson, David Howells, Ana Antonic, Tori O’Collins,Uli Dirnagl, H Bart van der Worp, Philip Bath, Mharie McRae, Stuart Allan, Ian Marshall, Xenios Mildonis, Konstantinos
Tsilidis, Orestis Panagiotou, John Ioannidis, Peter Batchelor, David Howells, Sanne Jansen of Lorkeers, Geoff Donnan,Peter Sandercock, Emily Sena, Gillian Currie, Hanna Vesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca,
Zsannet Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru,Stelios Serghiou, Aaron McLean, Catherine Dick, Tracey Woodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu,Sarah MaCann, Gillian Mead, Joanna Wardlaw, Rustam Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian
CAMARADES: Bringing evidence to translational medicine
Lessons for translation: SRMA in
understanding the pathogenesis of MS
Malcolm Macleod
Professor of Neurology and Translational Neurosciences
University of Edinburgh
and
Honorary Consultant Neurologist, NHS Forth Valley
Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies
CAMARADES: Bringing evidence to translational medicine
Multiple sclerosis
• Neuroinflammatory condition of 4 types:
– Clinically Isolated Syndrome
– Relapsing Remitting MS
– Secondary progressive MS
– Primary progressive MS
– Second leading cause of disability in young adults.
– Aetiology unknown, but thought to be related to genetic and
environmental factors
• Twin studies
• Season of birth
• Latitude
• Evidence of CMV infection
CAMARADES: Bringing evidence to translational medicine
Onset/ relapses
• Antecedent immune priming events not recognised (c.f. Guillain
Barre syndrome)
• Onset, and relapses, characterised by rapidly evolving symptoms
due to focal neurological dysfunction
• Caused by an acute, focal episode of demyelination affecting the
white matter tracts
• Resolution of symptoms as the acute inflammation fades and
remyelination occurs.
• Recovery from initial events often complete
• In time, recovery becomes only partial and disability accumulates
• Later, disability may progress in the absence of relapses
CAMARADES: Bringing evidence to translational medicine
Which T cell populations are
involved?
IL-
17
CAMARADES: Bringing evidence to translational medicine
Systematic review of in vivo data
• Experiments
– Testing interventions in animal models of EAE
– Reporting
• Neurobehavioural outcome
• Change in population of Th1 cells, or Th17 cells, or both
• Meta-analysis by “vote counting”
– For each outcome, was it
• significantly worse/ higher;
• significantly better/ lower
• no significant difference
• Coded red to green on 6 study quality indicators
Hammar, Unpublished
CAMARADES: Bringing evidence to translational medicine
• Th1 / behaviour – 16 experiments
• Th17/ behaviour – 17 experiments
CAMARADES: Bringing evidence to translational medicine
Immunisation EAETh17
Th1
CD4+
- = +
- 6
= 3
+ 6 1
EAE
Th
1
- = +
- 11 1
= 1
+ 2 2
EAE
Th
17
kappa = 9% (95% CI 0-29%) kappa = 38% (95% CI 0-84%)
CAMARADES: Bringing evidence to translational medicine
interpretation
• The severity of EAE is driven more by
Th17 T lymphocytes than by Th1 T
lymphocytes
CAMARADES: Bringing evidence to translational medicine
Developing treatments for MS
• There are now many
immunomodulatory treatments which
reduce relapse rate
• Some of these also appear to
influence surrogate markers which
may imply an effect on disability
progression
– Reduced MRI plaque burden
– Reduced rate of loss of gray matter
volume
• No established treatments for primary
or secondary progressive disease
CAMARADES: Bringing evidence to translational medicine
Can in vivo data tell us anything
about how drugs work?
inflammation
demyelination axon loss
CAMARADES: Bringing evidence to translational medicine
Can in vivo data tell us anything
about how drugs work?
• Publications identified in Vesterinen et al 2010
• 1152 publications describing efficacy of 1717
interventions
• From these, we selected 287 experiments which
had reported at least 2 different categories of
outcome
– Inflammation, demyelination, axon loss,
neurobehaviour
CAMARADES: Bringing evidence to translational medicine
Mediation analysis
R2 = 0.70
R2 = 0.70
R2 = 0.60
R2 = 0.70
R2 = 0.70
dR2 =
0.60-(0.70*0.70)
=0.11
CAMARADES: Bringing evidence to translational medicine
Inflammation
Axon LossDemyelination
Neurobehaviour
Drug efficacy
in MS
CAMARADES: Bringing evidence to translational medicine
Inflammation
Axon LossDemyelination
Neurobehaviour
Pre induction
1.000 1.000
CAMARADES: Bringing evidence to translational medicine
Post induction
Pre disease
Inflammation
Axon LossDemyelination
Neurobehaviour
0.625
0.077 0.088
0.206
0.232
0.140
0.004 0.562
CAMARADES: Bringing evidence to translational medicine
Inflammation
Axon LossDemyelination
Neurobehaviour
Disease
0.464
0.066
0.470
0.530
0.464
CAMARADES: Bringing evidence to translational medicine
interpretation
• In the early stages of EAE, before a behavioural deficit is
established, immunomodulatory drugs are highly effective
• This is concordant with their effects in relapsing remitting MS
• In later stages of EAE, immunomodulatory effects must also reduce
axon loss for there to be any behavioural benefit
• About half of the observed effects on behaviour in later stages
appears to be independent of drug effects on inflammation,
demyelination or axon loss
• Defining the characteristics of interventions which improve
behavioural outcome without improvements in inflammation,
demyelination (and perhaps axon loss) may define new targets for
drug treatment of primary and secondary progressive MS
CAMARADES: Bringing evidence to translational medicine
Thanks
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in vivo
Systematic Review
and Meta Analysis
Facility
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