PathogenesisofPsoriasisIntegra/ngPathogenesisandTreatmentofPsoriasis

AAD2017Structure&Func/onCourse

JimKrueger,MDPhDTheRockefellerUniversity

NY,NYjgk@rockefeller.edu

Conflicts•  Researchsupport,consul/ng,orlecturefeesbymostpharmaandbiotechcompanieswithapsoriasisproductorinves/ga/onalagent

•  Nopatents,ownership,orfinancialgainfromanypsoriasisproductordrug

•  Inthistalk,therapeu/cagentsarediscussedonlytoillustratediseasepathogenicmechanisms

Psoriasisvulgaris(2017mechanis/cdefini/on)

•  AnautoimmunediseasewhereIL-17inducesorregulatesauto-an/gensthats/mulateTh17(CD4+)&Tc17(CD8+)T-cellsand

•  WhereIL-17ac/vateskera/nocytesandothercelltypestoproduce“feedforward”cytokinesandotherinflammatorymoleculesthatcontrolepidermalhyperplasia,/ssuestructure,andmixedimmuneinfiltrates(dendri/ccells,T-cells,andneutrophils),includingother“polar”T-cellsubsetsthatac/velysynthesizeuniqueinflammatorycytokines.

•  Thuscutaneousimmunity,throughcytokineelabora/on,altersstructureandfunc/onoftheskin.

Canalsobeviewedasac/va/onofcellular/molecularpathwaysinducednormallytocontrolCandidainfec/ons

Unaffected Skin of Patient Psoriasis LesionUninvolvedSkin PsoriasisPlaque

CD3+T-cellsinPsoriasisUninvolvedSkin PsoriasisPlaque

EpidermalhyperplasiainpsoriasisistriggeredbyCD25+(ac/vated)T-cellsinterac/ngwithkera/nocytes

IGF-1KGFIL-6TGF-α

Homeostasis(lowprolifera/on&completedifferen/a/on)

Regenera/veGrowth(highprolifera/on&incompletedifferen/a/on)+Induc/onofimmune-relatedsurfaceproteins

CD40

(c.1995)

NON-LESIONAL PSORIASIS PLAQUE

H&E

CD11c

Myeloid(CD11c+)Dendri/cCellsinPsoriasis

CD3 cell counts

NL LS

0

50

100

150

200

250

300

350

CD11c cell counts

NL LS

0

100

200

300

400

500

600

Langerin cell counts

NL LS

0

25

50

75

100

125

8-foldaverageincrease 7-foldaverageincrease

p<0.0001 p<0.0001nosignificantchange

Conceptofaninflammatorydendri/ccell.CD11c+DCsinpsoriasisexpresshighlevelsofTNFandiNOS,andinaddi/onmakeotherkeyinflammatorycytokines

TNF

iNOS NitricOxide(NO)

TIP-DC TNF and iNOS Producing -DC (within CD11c+ or myeloid DC subset in psoriasis lesions)

iNOS

TNF

TRAIL

TLR1&TLR2

TIP-DC(InflammatoryCD11c+DC)extendedphenotype

S100A12

IL-20

IL-23

InflammatoryDendri/cCellsinPsoriasisLesions

IL-17IL-22

Th17

Th2

Th1Tc1

IL-4IFN-γ

IL-12andIL-23--“p40”cytokines--controlac/va/onof“polar”T-cellsubsets

IL-12 IL-23

Th22

p40

1.0

10.0

100.0

1,000.0

10,000.0

Rela

tive G

en

e E

xp

ress

ion

p19

1.0

10.0

100.0

1,000.0

10,000.0

Rela

tive G

en

e E

xp

ress

ion

Consistentup-regula/onofp40andp19mRNAs(IL-23subunits)inpsoriasisplaques,asdetectedbyreal-/meRT-PCR(normalizedtoHARPmRNA)

uninvolved uninvolvedlesion lesion

p<0.000001

LeeetalJEM(2005).Inthiswork,IL-23synthesistracedbacktoCD11c+DCs

Th1

Th17

Blood

PsoriasisLesion

Th17T-cellsincreasedinpsoriasislesions

Geneexpressionduringcyclosporinetreatment

What features of psoriasis may be explained by Th17 T-cell products

(especially IL-17 and IL-22)?

S100A9(calgranulinB)

S100A7(psoriasin)

Normal LSPsoriasis

Whatispoten/alsignificancetoac/vatedTh17T-cellstobiologyofpsoriasislesions?

Wolketal.Eur.J.Immunology(2006)

IL-22

S100A7(psoriasin)S100A8S100A9&profilaggrinStronglyinducedbyIL-22,notbyγ-interferon

humankera/nocytes

(invitro)

Innate defense molecules FCH DEFB4 defensin, beta 4 238.549S100A7 psoriasin 189.381S100A12 S100 calcium binding protein A12 30.707S100A8 S100 calcium binding protein A8 1.575S100A9 S100 calcium binding protein A9 2.149

Cytokines FCH IL1F9 interleukin 1 family, member 9 15.062IL8 interleukin 8 14.529IL1B interleukin 1, beta 2.732

Chemokines FCH CCL20 chemokine (C-C motif) ligand 20 28.306CXCL6 chemokine (C-X-C motif) ligand 6 26.15CXCL1 chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha)7.688CXCL2 chemokine (C-X-C motif) ligand 2 6.006CXCL5 chemokine (C-X-C motif) ligand 5 5.643CXCL3 chemokine (C-X-C motif) ligand 3 3.812

NogralesKEetal,BriMshJournalofDermatology,2008

Genesup-regulatedbyIL-17inkera/nocytes

media IL-19 IL-20 IL-22 IL-24 EGF

Kera/n16

S100A7(psoriasin)

STAT3

Saetal.JImmunol(2007)

IL-22s/mulates:AcanthosisofepidermisKera/n16S100A7(Psoriasin)STAT3nucleartransloca/on

IL-17andIL-22inducekeymolecularfeaturesofpsoriasis

IL-22

IL-17

IL-22promotesacanthosisandimpairsterminaldifferen/a/on

NogralesKEetal,BriMshJournalofDermatology,2008

Fullthicknessskinrans(epidermis+fibroblasts/dermis)

§ ConfirmseffectofIL-22onacanthosisofepidermis(SaetalJImmunology2007)§ *Parakeratosis

*

The TIP-DC è IL-23 è Th17-Th22 Pathway

Th17

Keratinocytes have unique responses to IL-17 & IL-22. Effects are distinct from those of Th1-cytokines.

IL-23

IL-17

IL-22 (& other IL-20

family cytokines)

TIP-DC S100A7 “psoriasin”

parakeratosis

Th22

Th1, Th17 andTh22 T-cells drive cellular and molecular features of psoriasis trough complex cytokine circuits

An/microbialpep/desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20

Th1

Th17

Th/Tc22

IL-23(p40/p19)

IL-12(p40/p35) TNF-α

IFN-γ

IL-17A/FIL-21

IL-22

kera/nocyte

kera/nocyte

NKTcell

plasmacytoidDendri/ccell

macrophage

acMvaMon

IL-1βIL-6

TNF-αTNF-αIFN-γ

TIP-DCIFN-α

TNF-α

LESIONFORMATION

Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509

The IL-23/Th17 axis is essential sustaining disease activity

An/microbialpep/desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20

Th1

Th17

Th/Tc22

IL-23(p40/p19)

IL-12(p40/p35) TNF-α

IFN-γ

IL-17A/FIL-21

IL-22

kera/nocyte

kera/nocyte

NKTcell

plasmacytoidDendri/ccell

macrophage

acMvaMon

IL-1βIL-6

TNF-αTNF-αIFN-γ

TIP-DCIFN-α

TNF-α

LESIONFORMATION

Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509

IL-23/Th17 pathway in psoriasis

neutT17DC

KC

Tcell DC

IL-23 IL-17

CCL20

CCR6+cells

CXCchemokinesCXCL1,2,3,5IL-8

An/-microbialpep/desβ-defensinsLipocalinLL-37S100A7,S100A8

Th17Tc17Tgamma-delta17ILC17

0102030405060708090100

0 4 8 12 16 20 24MeanIm

provem

entinPA

SI(%

)

Week

Placebo BI655066i.v. BI655066s.c.

DrugAdministraMon(singledose)

ChangesinPASIscoresfollowingasingleadministra/onofBI655066orPlacebo

27*i.v.ands.c.BI655066groupscombined

Week12*PASI75=87%PASI90=58%

p<0.01vs.Placebo(0%)

BI655066isahumanp19monoclonalan/body(IL-23blocker)DatapublishedMarch2015J.AllergyClinImmunol(online).

ClearingofPsoriasisLesionswithBI655066

29

Week 0 Week 12

Consistentimprovementsinpsoriasisinducedbymul/pleIL-23antagonists

•  Guselkumab(humanan/bodytop19subunit)

•  Tildrakizumab(humanan/bodytop19subunit)

•  BI655066(humanan/bodytop19subunit)

IL-23/Th17 pathway in psoriasis

neutT17DC

KC

Tcell DC

IL-23 IL-17

CCL20

CCR6+cells

CXCchemokinesCXCL1,2,3,5IL-8

An/-microbialpep/desβ-defensinsLipocalinLL-37S100A7,S100A8

Th17Tc17Tgamma-delta17ILC17

Study Design

SC=subcutaneous;W=week

Study Treatment Period Screening

Period

Placebo SC (n=8)

Ixekizumab 15 mg SC (n=8)

Ixekizumab 50 mg SC (n=8)

Ixekizumab 5 mg SC (n=8)

W2 W0 W16 W4 W12 W6

Dose 1 Dose 2 Dose 3

W20 End of Study

Ixekizumab 150 mg SC (n=8)

All Subjects

Study Period

Follow Up

Biopsy Biopsy Biopsy

Expression of IL-17 Target Genes (RT-PCR)

log2(expression/hARP)=mRNAexpression(RT-PCR)normalizedtothehousekeepinggenehumanacidicribosomalproteingene(hARP)

Lipocalin2 Interleukin8

β-defensin2 CXCL1

Immunohistochemical Analysis of Skin Biopsy (150 mg ixekizumab)

Proportion of Patients with PASI 75

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20

Placebo SC (n=8) LY 150 mg SC (n=8)

Dose Dose Dose Weeks

Prop

or/o

nof

Pa/e

nts

Genes Modulated by ixekizumab (FCH>6)

LS=LesionalSkinBiopsiesatBaseline

NL=Non-LesionalSkinBiopsiesatBaseline

Psoriasis Lesions at Weeks 0, 2 and 6 Placebo, Baseline Placebo, Week 2 Placebo,Week6

Ixekizumab 150 mg, Baseline

Ixekizumab 150 mg, Week 2

Ixekizumab 150 mg, Week 6

Kruegeretal.Brit.J.Derm.FC-13.2011;165:1157-1366.

Consistentimprovementsinpsoriasisinducedbymul/pleIL-17antagonists

•  Secukinumab(an/-IL17monoclonalan/body)

•  Ixekizumab(an/-IL-17Amonoclonalan/body)•  Brodalumab(an/bodytoIL-17ReceptorAsubunit,blockingIL-17A&IL-17Fsignaling)

WhatistheroleofTNFinthepathogenesisofpsoriasis?

IL-23

TNF interacts with the IL-23/Th17 pathway at two points. First, TNF induces IL-23 production in myeloid DCs. Second, TNF & IL-17 interact synergistically and additively in keratinocytes to increase transciption of many psoriasis-related genes

DC

neutTh17KC

Tcell DC

IL-17

CCL20

CCR6+cells

CXCchemokinesCXCL1,2,3,5IL-8

An/-microbialpep/desβ-defensinsLipocalinLL-37S100A7

TNF

SeveralhundredgenesInducedbyIL-17+TNF:Synergis/candAddi/veEffects

TNF

o  InvitroNormalHumanKera/nocytesgrowthwithmedium

o  Treatedfor24hwith:

–  Mediumalone

–  IL-17200ng/mL

–  TNF10ng/mL

–  IL-17+TNF10

o  GenesequencingbyIlluminaGenechip

o  RT-PCR

TNF

IL-17 IL-17+TNF

Control

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Correla/onwithpsoriasistranscriptome1

1YaoYetal.PlosOne2008

Genes synergis/cally induced by IL17and TNFα resulted overexpressed inpsoria/clesionalskinThey strongly correlatedwith psoriasistranscriptome

PsoriasisTranscriptome(LevelofGeneExpression)

Syne

rgis/

cGe

nes

(ExpressionLevel)

r=0.79p<10-10

Pathway: TNF è IL-23 è IL-17 (single and synergistic effects) But, how do we get from IL-17 to a complex tissue phenotype?

An/microbialpep/desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20

Th1

Th17

Th/Tc22

IL-23(p40/p19)

IL-12(p40/p35) TNF-α

IFN-γ

IL-17A/FIL-21

IL-22

kera/nocyte

kera/nocyte

NKTcell

plasmacytoidDendri/ccell

macrophage

acMvaMon

IL-1βIL-6

TNF-αTNF-αIFN-γ

TIP-DCIFN-α

TNF-α

LESIONFORMATION

Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509

NON-LESIONALLESIONALKi-67

S100A7

psoriasin

NON-LESIONALLESIONAL

HBD-2(β-defensin)

LCN-2(lipocalin-2)

New age of molecular medicine where translational research will

accelerate therapeutic development for many different skin diseases

UnderstandingofPathogenesis

TargetedTherapeu/cs

Ideaof“digital”inflammatorydiseases•  Psoriasisvulgaris–AnIL-17dominatedinflammatory

disease(Type17T-cells)withco-ac/va/onTh1andTh22T-cellswithCD11c+DCs

•  Atopicderma//s–AnIL-4/IL-13dominatedinflammatorydisease(Th2T-cells)withco-ac/va/onofTh1andTh22withCD11c+DCs

•  CutaneousLupus–Aninterferondominatedinflammatorydisease(Th1T-cells)andco-ac/va/onofinnateinterferonproducingcells(myeloidandplasmacytoidDCs)

Thankyou