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Rutgers, The State University of New Jersey

Suhayl Dhib-Jalbut, MD

Professor and Chairman

Department of Neurology

New Insights in MS Immunopathology: Inflammation, is it

all bad?

Inflammation in MS: Is there Balance?

Modifies after Yong Neuroscientist, 16:408

► Neuroprotection► Axonal

Regeneration► Neurogenesis► Remyelination

► Injury to neural elements

► Death of neurons and oligodendrocytes

► Inhibition regenerative processes

BeneficialOutcomes

DetrimentalOutcomes

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MS

Immune Dysregulation

Genetic Predisposition

-Twins studies

-HLA-DR2 (DRß1*1501)(antigen presentation)

-IL-2Ra(regulatory T-cells)

-IL-7Ra(memory T-cells)

GWAS (>100 alleles)

Environmental Factors

Demographics/Epidemics

Microbial Agents

EBV

Vit. D

Smoking

Salt

Microbiome

Multiple Sclerosis: An Immuno-genetic Disease

Dhib-Jalbut, S 2013

Helper T cell differentiation

IL-12/STAT4 IFN- Pro-inflammatoryTH1

TH2

IL-4

IL-5

IL-10

IL-13

Anti-inflammatory/

AllergyIL-4/STAT6

IL-23

IL-17 Pro-inflammatoryTH17IL-6 + TGF-β

TGF-β RegulatoryTreg

TGFβ

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NOOiTNFMMP

T

IL-10TGF

Tr1Th2Th3

CD4+CD25+

IL‐6

TregFoxp3TGFß

TregFoxp3

TregFoxp3

?EBV

FcR

Glutamate

B7

CD40

IL‐17

DC

Neut

IL‐17

IL‐23

Th17Th17

CCR6

CCL20

IL-6 & TGF-ß

APCThp

Pl Ab+C9neo

Tr1Th2Th3

IL-4IL-5IL-10IL-13TGF-

B

BAFFAPRILTACI

CD40L

CD28

CD40

IL-4 & IL-10

CD4APCThp

B7

IFNTNF

MCP-1MIP-1P-10RANTES

Astrocyte

CD40L

CD28

Th1

ICAM-1

MMP-2/9VCAM-1

IFNTNFLFA-1

Th1VLA-4

BBB

Oligo

Immunopathogenesis of MS (2014) Courtesy of Suhayl Dhib‐Jalbut, MD

IL-12

APC

Thp

CD4

Myelin AgMicrobial Ag

HLATCR

IL‐1TNF

TLR

B

CD8CTL

CD8CTL

CD8p

Oligo

Immunopathogenesis of MS

Ab+C9neoRNOROSTNFMMP

Dhib-Jalbut, S 2014

B7

CD40 CD40L

CD28

Th1

Glutamate

CD8CTL

IFNgTNF

MMP-2/9

BB

PLOligoo

BBB

MCP-1MIP-1aIP-10RANTES

Astrocyte

BBIFNgTNF

Th1VLA-4

ICAM-1VCAM-1

Th0APC

Myelin AgMicrobial Ag

HLATCR

IL-4IL-5IL-10IL-13TGF-b

IL-10TGFb

TregFoxp3

Tr1Th3

IL-6 & IL1-ß

IL-23IL-17

TGFß

IL-6

TregFoxp3

TregFoxp3

CD8p

?EBV

FcR

CD8Reg

CCR6CCL20

DC

Th17Th17Th17Th17

Th17Th17

NeutNeut

S1Pr

S1Pr

S1Pr

TLR

Fingolimod

IFNBNatalizumab

GA

GA

Fampridine K+

IFNBGA

GA

Rituximab

Tr1Th3

Th2

Th0Th0 IL-4

IL-12

B7-CD28

S1PrTFL

BG-12

CD20

BG-12

Epitopespreading Oligo

AlemtuzumabMitoxantrone

Vit D

KIR4.1

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Marker CIS RRMS SPMS PPMS

Cytokines IL12,TNF,IL6sTNFR, IL10

Treg (CD39) Decreased Normal

B-cells(CD19) ++/CSF ++/CS - -

CXCL3 ++ ++ - -

Anti Glycan IgM

+ -

MMP9/sICAM

++

BDNF + Decreased

S100b (CSF) +

NAA (CSF) ++ -

Osteopontin +++ + +

Cont/FeutinVit.D, ANGT

- + -

Fibulin + + -

Summary of Inflammatory markers by disease stage

Immunopathogenesis of MS

Inflammation

Regeneration

Inflammatory Processes Occurring Early in MS Leadto Demyelination and Axonal Loss

TimeOnset of Disease Inflammation Demyelination Axonal loss

Compston A, et al. Lancet. 2008;372:1502-1517. Kuhlmann T, et al. Brain. 2002;125:2202-2212.Paolilo A, et al. J Neurol. 2004;251:432-439.Trapp BD, et al. Curr Opin Neurol. 1999;12:295-302.

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Gray Matter Lesions in MS

Axonal Transection

Type 1 Type 2 Type 3

Neuronal Apoptosis

Trapp and Nave Ann Rev Neurosci 31:247

Pathogenesis of Neurological Dysfunction:Axonal Transection and Degeneration

Inflammatory demyelination followedby Na+ channel redistribution and remyelination leading to restorationof conduction and clinical remission

Axonal transection resulting in degeneration of the distal axonal segment or loss of trophic support of demyelinated axons leads to loss of neuronal function.

Trapp; Neurocscientist 5:48

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Microglia induce focal axonal swellings by releasing reactive oxygen and nitrogen species (ROS and RNS)

Picture from Axonal injury in reverse by Craner & Fugger

Courtesy of Wee Yong

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Modifies after Yong Neuroscientist, 16:408

Proposed Protective Effects of Lymphocytes and Microglia

Removal ofDebris

Release NeurotrophicFactors

Neutralize Toxic Products

Overcome Inhibitory ECM

Mobilize Astrocytes

Removal of non-permissiveproteoglycans

Stabilize BBB Trophic Support

Axtell & Steinman, Immunity 28:675, 2008

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Factors Affecting Remyelination and Oligodendrocyte Recruitment

► Failed oligodendrocyte precursor cell differentiation:● An untimely transition of the acute inflammatory to

a chronic inflammatory environment● Prolonged presence of early inhibitors ● A premature expression of late inhibitors of

oligodendrocyte precursor cell differentiation● Combinations of the above

► Expression of factors that induce astroglial fate of oligodendrocyte precursors

(1)Hinks and Franklin, 1999; (2) Shields et al., 1999; (3) Marin-Husstege et al.;2002;(4) Shen et al., 2005 (5) Nakahara et al 2009;

Strategies to Promote CNS Remyelination in MS

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Examples of Remyelination in Experimental Models

Control Cup + H2O Cup + Fing

Effect of Fingolimodin the Cuprizone Model (3)

(1) Lin et al. Brain 129:1306; (2) Skihar PNAS 106:17992; (3) Kim et al Faseb J. 25:1509

Effect of IFN-gammain the Cuprizone Model (1)

Effect of glatiramer acetatein the Lysolecithin Model (2)

Strategies to Promote CNS Remyelination in MS

Target/Strategy Agent Pre-clinical Clinical

Inhibition of LINGO-1 LINGO-1 inhibitor Mi et al., 2009 yes

Inhibition DR-7 DR-7 inhibitor Mi et al., 2011

Anti myelin basic

protein E2 137-151

Anti-E2 137-151or E2 137

151 peptide

Patent application

20090311246

Antibody-based rHIgM22 antibody Pirko et al., 2004

Neutralization of myelin

associated inhibitors

RhoA inhibitors/PKC inhibitors

Baer et al., 2009

Inhibition of St8SiaIV (PSA) Koutsoudaki et al., 2010

Inhibition of Notch1 Zhang et al., 2009

Oestrogen-receptor ligand

Crawford et al., 2010

Induce oligo’s to remyelinate

HIgM22 Rodriguez et al., 2009 Filed 2012 ?

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Effect of anti-Lingo in EAE

Mi et al Nat Med 13:1228

Regulatory Cells

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CD4+CD25+ Regulatory T-cells in MS

• Reduced suppressive function in MS

• No difference in frequency between MS and controls

• No difference in cytokine secretion patterns (IL-10, TGFß)

Viglieta et al. J Exp Med 2004;199:971

Induction of CD4+CD25+FOXP3+ Regulatory T cells During GA Treatment

CD4+CD25+FOXP3+

CD4+CD25+FOXP3-

Pre-Rx 3mo 6mo 12mo18-24mo

Pre-Rx 3mo 6mo 12mo 18-24mo

Dhib-Jalbut, S. 2008

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Induction of CD4+CD25+FOXP3+ TregsDuring Glatiramer Acetate Treatment

0.0

2.5

5.0

7.5

10.0CD4+CD25+FoxP3+

Mean GA-R

Pre-Rx 3mo 6mo 12mo 24mo

% g

ated

in

CD

4+ c

ell

s

0.0

2.5

5.0

7.5

10.0CD4+CD25+FoxP3+Mean GA-HR/NR

Pre-Rx 3mo 6mo 12mo 24mo

% g

ated

in

CD

4+ c

ells

Dhib-Jalbut S, et al. 23rd Congress of ECTRIMS, 12th Conference of Rehabilitation in MS;October 11-14, 2007; Abstract ID 52136.

Modulation of Tregs by therapy in MS

Saresella et al. FASEB, 22:3500, 2008

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Feed Your Tregs More Fiber

Julia Bollrath and Fiona Powrie. SCIENCE VOL 341 2 AUGUST 2013

Microbiome: Gut-Brain Axis

Healthy State:Satiation peptidesGut motilityGut permeabilityGut secretion(e.g. endocrines,AMPSs, mucins)Immune cellsCytokines, IgAs

Downward Control Upward Control

Alteration of gut microbiota

Microbiota composition Symbiotic vs. Pathogenic

Microbiotics-derived products

Dietaryintervention

Exogenous AntibioticsExogenousProbiotics

Healthy State:Neuro-development

Disease stateNeuro-immune disorders(e.g. MS, NMO, GBS)

Neuro-psychiatric disorders(e.g. ASD, depression,anxiety, stress, defects inmemory and cognition,co-morbidity with IBS andIBD)

Upward Control

Wang Y. and L. Kasper. Brain Behav Immun. 2013. Dec 25. pii: S0889-1591(13)00600-4. doi: 10.1016/j.bbi.2013.12.015. [Epub ahead of print]

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Dalia Raïch-Regué et al., Immunology Letters, 2013

Regulatory Dendritic Cells

Biswas & Mantovani, Nature Immunologyvolume 11 number 10 october 2010

Macrophage Polarization

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Mikita et al, Multiple Sclerosis Journal17(1) 2–15, 2014

Altered M1/M2 activation patterns ofmonocytes in severe relapsingexperimental rat model of multiplesclerosis. Amelioration of clinical status byM2 activated monocyte administration

Pharmacologic modulation of glial cells

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Targeting the Shift from M1 to M2 Macrophages inExperimental Autoimmune Encephalomyelitis MiceTreated with Fasudil

Liu et alPlos One2013

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Starossom et al. Immunity 37, 249–263, August 24, 2012

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MODI et al. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 25, pp. 18533–18545, June 21, 2013

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Summary-Beneficial inflammation

● T-regulatory cells

● M2 Polarization

● Regulatrory DC

● Microglial function modulation

● Astrocyte modulation

● Neurotrophic factors

Inflammation: Favorable & detrimental factors

Kantarci et al. Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 1 januar y 2014

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Thank You