Pathogenesis of Psoriasis Integra/ng Pathogenesis and Treatment of Psoriasis AAD 2017 Structure & Func/on Course Jim Krueger, MD PhD The Rockefeller University NY, NY [email protected]
PathogenesisofPsoriasisIntegra/ngPathogenesisandTreatmentofPsoriasis
AAD2017Structure&Func/onCourse
JimKrueger,MDPhDTheRockefellerUniversity
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
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)
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
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-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).
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
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)
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
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)