#11 Multiple Sclerosis

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Multiple Sclerosis: FromMultiple Sclerosis: From

Bedside to Bench andBedside to Bench andBack AgainBack Again

Jeri-Anne Lyons, Ph.D.

Department of Health Sciences

University of Wisconsin-Milwaukee


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Central Nervous SystemCentral Nervous System

DiseasesDiseases

& Neurodegeneration& Neurodegeneration Multiple Sclerosis

Immune-mediated

Destruction of themyelin sheath & axonsin the central nervoussystem

Signs and symptomsdepend on thelocation, size, andnumber of lesions(plaques)

Four main clinicalsubtypes

Hallmarks of disease Periventricular lesions

Mononuclearinflammatory cells +/-antibodies

Demyelination Relative axon sparing

Astrocyte hypertrophy Cervical spinal cord

disproportionatelyinvolved


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Demographics of MSDemographics of MS

Average age of onset 15 to 45 years1

Gender ~70% women2

Geography Incidence increases with distance from

equator in both directions 3

Incidence 8,500 to 10,000 new cases per year2

Prevalence 0.1% of US population (350,000)2

Race Caucasians > other ethnic groups

1. Anderson DW et al.Ann Neurol. 1992;31:333-336.

2. Jacobsen DL et al. Clin Immunol Immunopathol. 1997;84:223-243.3. Hauser SL. HarrisonsPrinciples of Internal Medicine. 1994.


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Etiology of MultipleEtiology of Multiple

SclerosisSclerosis

Adams, Victor. Principles of Neurology. 5th ed. 1993;776-798

Environmental Factors

Familial tendency

Susceptibility

genes

infectious agent (s)

Autoimmunereaction


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MS LesionsMS Lesions


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Adapted from Lublin FD, Reingold SC. Neurology. 1996;46:907-911;

Disease Course in MSDisease Course in MS

* Jacobs et al. Mult Scler. 1999;5:369-376.

(55%)*

(30%)*

(10%)*

(5%)*


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Clinical Course vs.Clinical Course vs.

PathologyPathology

DiseaseSeverity

Time (months/years)


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Diagnostic TestsDiagnostic Tests

Magnetic resonance imaging (Brain and Spinal cord-

especially cervical cord)

Analysis of spinal fluid

Evoked potentials (visual, brainstem/auditory,

somatosensory) used less often


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MRI of normal vs. MSMRI of normal vs. MS

BrainsBrains


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Evidence for ImmuneEvidence for Immune

SystemSystem

Involvement in MSInvolvement in MS Inflammation

CSF humoral dysimmune phenomena

Peripheral blood dysimmune phenomena

HLA (major histocompatibility) types associated with

susceptibility

Female predominance (3:2)Response to immunomodulatory agents

Animal models

Neuroimmunology Section, Washington University


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Antibody Abnormalities inAntibody Abnormalities in

CSF with MSCSF with MS

Increased CSF Index

IgG CSF/albumin CSF

IgG serum/albumin serum

Increased IgM and IgG

synthesis rate

Oligoclonal bands

**http://library.med.utah.edu/kw/ms/mml/ms_oligoclonal.html

John Rose, M.D., Maria Houtchens


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Send in the murines

Research in an animal model


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Experimental AutoimmuneExperimental Autoimmune

Encephalomyelitis (EAE)Encephalomyelitis (EAE)

Inflammatory demyelinating disease of the CNS Primary animal model for MS Autoimmune response to myelin proteins mediated by

CD4+ Th1 T cells Induced by active immunization with myelin proteins

Myelin Basic Protein (MBP) Proteolipid Protein (PLP) Myelin Oligodendrocyte Glycoprotein (MOG)

Disease characterized by ascending paralysis beginningapproximately 14dpi or 10dpt Pathology predominantly observed in lumbar region of the

spinal cord


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EAE in Various SpeciesEAE in Various Species

and Strainsand StrainsLewis RatsB10.PL mice

MBP

(MBPAc1-11)

SJL mice

Marmoset

(Callithrix jacchus)

PLP (PLP139-151)

MBP (MBP89-106)

MOG (MOG92-106)

MOG (MOG24-46)

C57BL/6 mice

BALB/c mice

MOG (MOG35-55)

PLP (PLP180-199)


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M O G ( 3 5- 5 5) im m

012

345

0

17

24

27

32

35

39

42

46

D a y P o s t I m m u

ClinicalS

core

rMOG immunization

0 10 20 30 40

0

1

2

3

4

5WT

B cell-/-

Day Post Immunization

ClinicalSc

ore

rMOG vs. MOGrMOG vs. MOG35-5535-55 induced EAEinduced EAE

in WT vs. B cellin WT vs. B cell-/--/- micemice


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Reconstitution of EAE in B cellReconstitution of EAE in B cell-/--/- micemice

WT B6mouse

Immunizew/ Ag

14-16d later,collect serum

(Ab) and remove

spleens (for Bcells)

B cell-/- B6mouse

Immunizew/ Ag

Observe for EAE


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Clinical EAE in B cellClinical EAE in B cell-/--/- mice:mice:

rMOG B cellsrMOG B cells

0 10 20 30 40 500

1

2

3

4

5

rMOG CD19+ B cell recipients

WT Controls

rMOG CD19+ CD80+B cell recipients

B cell-/- controls

day post immunization

MeanClinicalScore


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Clinical EAE in B cellClinical EAE in B cell-/--/- mice: rMOGmice: rMOG

serum Abserum Ab

0 10 20 30 40 500

1

2

3

4

5

WT B6

B cell-/-rMOG serum recipients

B cell-/- controlreceived serum 31dpi

receivedserum:

day post immunization

meanclinical

score

B R


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Potential Roles for B cells in EAE/MSAdvantageous Harmful

B cells Alter T cellresponse

(Th1 Th2)

Initiate T cell response

(Ag proc./presentation;costimulation)

Antibody Remyelination Recruit Cells to CNS

Demyelination

Opsonization

C activation

BcR

B cellPlasma

Cell

Antibody

Bind

Ag

Other

Functions

BcR

B cellActivated

other immune functions


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Taking it back to the clinic


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RituximabRituximab

Mouse/human chimeric antibody vs. CD20

Targets pre-B cells & mature B cells

Spares stem cells, plasma cells Complement-mediated lysis

FDA-approved for treatment

1997: B cell lymphoma

2006: Rheumatoid Arthritis Early studies suggest successful as monotherapy in

Relapsing-Remitting MS


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Patient PopulationPatient Population


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Treatment Protocol


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ResultsResults

Prolonged depletion of B cells

Decreased MRI activity

Some clinical effect observed

No effect on CSF immunoglobulinsSynthesis or oligoclonal bands


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Surprising Results


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Summary

Multiple sclerosis is an autoimmune

demyelinating disease

Disease is initiated by myelin-reactive T cells

B cells and antibody are important to disease

pathology

Targeting B cells may be an effective therapy in

those patients not responding to current therapy


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AcknowledgementsAcknowledgements

Washington University

Dr. Anne Cross

Dr. Rob NaismuthDr. Laura Piccio

Michael Ramsbottom

#11 Multiple Sclerosis

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