Immunology and the roots of MS

MS Trust Annual Conference 2012 For health and social care professionals

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

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Current Dogma

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis - biology

Current Dogma

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis - biology

Clinical Attack

Disease Progression

Clinical Recovery

- clinical outcomes

Current Dogma

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis - biology

Clinical Attack

Disease Progression

Clinical Recovery

- clinical outcomes

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

- biomarkers

Current Dogma

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Current Dogma

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

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Interferon-beta Glatiramer acetate

Mitoxantrone Natalizumab

Fingolimod Teriflunomide Alemtuzumab

BG12 Cladribine

Rituximab/Ocrelizumab Daclizumab

Martino et al. Lancet Neurology 2002; 1:499-509.

RRMS: pathology of the newly forming lesion

Barnett & Prineas. Ann Neurol 2004;55:458–468.

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Post-inflammatory neurodegeneration

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Neuroprotection

Rationale for sodium channel blockade

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41. Videos courtesy Hugh Bostock, Inst. Neurol., UCL

Bechtold et al. Ann Neurol 2004;55:607–616

Secondary progressive EAE

Pryce et al. Brain 2003;126:2191-202.

Time (Days)

10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

Mea

n C

linic

al S

core

± S

EM

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Vehicle Cannabinoids

TREATMENT

Neuroprotection

Aims of CUPID study

• to assess the value of Δ9-THC in slowing progressive MS over 3 years.

• to assess the safety of Δ9-THC over the long-term. • to improve research methodology by using new,

patient-orientated methods.

Slide courtesy of Prof. John Zajicek

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

Slide courtesy of Prof. John Zajicek

Year 3 Year 4 Year 5

560 MS’ers

280 MS’ers with PPMS or SPMS

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis Registration

Not 7 years, but 10 years

Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID)

280 MS’ers with PPMS or SPMS

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.

Neuroprotective targets

Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.

Spinal fluid neurofilament levels

Recruitment Trial Data analysis

6 months

6 months 60 MS’ers

6 months

LP2 LP3 LP4

30 MS’ers active tablet

30 MS’ers placebo tablet

2 years

6 months

LP1

38 year old woman with left optic neuritis

sTE fFLAIR images

Baseline 52 weeks

Hickman et al. Neuroradiology 2001;43:123-8.

Trapp et al. N Engl J Med 1998.

Acute mono-focal lesion

CFM6104 Induces Neuroprotection in Optic Neuritis (Nerve Content)

Reduced Nerve Damage

Normal mouse

Mea

n r

etin

a ce

ll d

ensi

ty (

cells

/mm

2)

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

OPTIC NEURITIS

+ Vehicle OPTIC NEURITIS +

CFM6104

P<0.01

NEUROPROTECTIVE STRATEGIES IMMUNE-DEPENDENT

NEURODEGENERATION

Acute neuroprotection

Ischemic penumbra

Ischemic penumbra

Neu

rop

rote

ctio

n

Time Post-Disease Induction (days).

32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Vehicle

CFMA D33-D48 Hindlimb

Paralysis

Hindlimb

Paresis

Impaired

Right

Reflex

Tail Paresis

Tail

Paralysis

Period of Daily Treatment

No Immunosuppression Evident

ROTAROD ACTIVITY

Measure of Motor Co-ordination

Pre-Treatment (Day 27)

0

50

100

150

200

250

300

Post- Relapse (Day 48)

***

Neu

ropr

otec

tion

Mea

n N

euro

logi

cal

Sco

re ±

SEM

Tim

e of

on

Acc

eler

atin

g R

otaR

od (

s)

CFMA Induces Neuroprotection in EAE

Immunologic penumbra

Is the current dogma wrong?

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Is the current dogma wrong?

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Is the current dogma wrong?

immune activation innate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Virus?

Genes

Environment Chance

MS is a complex disease

Ramagopalan, Dobson, Meier, Giovannoni. Lancet Neurol. 2010 Jul;9(7):727-39.

MS Endophenotype

Conclusions • MS is complex disease

– The immune system is clearly involved (primary or secondary)

– MS endophenotype (imprinting beginning in utero) suggests MS may be a preventable disease

• Has the emergence of monoclonal therapies cracked the relapsing or inflammatory phase of the disease?

• Progressive MS remains a problem

– The challenge is doing affordable phase 2 & 3 trials

– We need new outcome measures and clinical trials

• Is the immunological dogma wrong?

– Is MS ready for a paradigm shift; for example anti-viral therapies?

– The Charcot Project

• www.ms-res.org

www.ms-res.org