translational research & developmentcyclic nucleo tide phos phodi esterases (pdes) cyclosp o rin...

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h t a e D f o y e l l a V & h c r a e s e R l a n o i t a l s n a r T t n e m p o l e v e D c i s a B h c r a e s e R l a c i n i l c e r P t n e m p o l e v e D l a c i n i l C t n e m p o l e v e D w e i v e R y r o t a l u g e R l a v o r p p A l a i c r e m m o C h c n u a L

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Page 1: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

htaeD fo yellaV & hcraeseR lanoitalsnarT

tnempoleveD

cisaBhcraeseR

lacinilcerPtnempoleveD

lacinilCtnempoleveD

weiveR yrotalugeRlavorppA

laicremmoChcnuaL

Page 2: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

egnahC & ytixelpmoC fo sreyaLyellaV eht ni segnellahC

• setebaiD• yrevocsiD

• yrotalugeR• tnempoleveD• ssenisuB

• scimonocE• tekraM ot emiT• noitacudE• noitatnemelpmI• noitargetnI

hcaeR cimedipE – M582 ot esolc gnitceffa cimedipe labolg a deredisnoc won si setebaiD eht ni M72 ,anihC ni M34 ,aidnI ni M05 revo gnidulcni ,)noitalupop s’dlrow eht fo %7( elpoep

gnidolpxe si setebaid 2 epyT fo ecnedicni ehT .tsaE elddiM eht ni M61 revo dna ,SUerehwyreve tsoC hgiH – labolg fo %21 ,B573$ fo ssecxe ni si smetsys erachtlaeh labolg ot tsoc llarevO

serutidnepxe erachtlaeh

& etalsnarTetareleccA

Page 3: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

seigetartS gnirentraPnoitareleccA & noitalsnarT

secivreS cigetartStnempoleveD lacinilC & yrotalugeR

ni tnemeergA noitaroballoC dehsilbatsEaibarA iduaS

wen ,stessa ot ssecca egareveL rof troppus ssenisub dna ,seitinutroppo

noitalsnart tnempoleved & noitarelecca

,spihsnoitaleR ,esitrepxE egareveLsevitaitinI labolG dna ,seitinutroppO

daehrevo wol ,enilepip elbaiVADF - noitpo tsal

noitargetni & snoitanibmoc levoN

,ytisebO ,setebaiD cilobateM

esaesiD

adanaC nilusxEaibarA iduaS nilusxE

Page 4: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

• fo tnemevorpmi setartsnomed )editpeP PAGNI( ™nilusxEsledom lamina elpitlum ni lortnoc cimecylg

• srotaludom enummi htiw noitanibmoc ni editpeP PAGNI lamron gninruter setebaid 1T fo noissimer lluf setartsnomed

fo noitareneger swohs & sledom lamina 1T ni lortnoc cimecylgstelsi

• namuh a ni noitareneger telsi setartsnomed editpeP PAGNI gnidulcni noitcnuf telsi lamron fo nruter a dna ledom eussit

nitatsotamos & ,nogaculg ,nilusni

• htob fo slairt namuh ni ytivitca setartsnomed editpeP PAGNIsetebaid 2T dna 1T

tegraT citueparehT tnenimeerPseirogetaC ruoF ni ecnedivE gniworG

Page 5: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

setebaiD 1 epyT dehsilbatse no tsriF sucoF raelc ,deen temnu hgih fo esuaceb htap yrotaluger gnignellahc ssel dna ,tegrat tniopdne

sa PAGNI fo ytilibarelot dna ycaciffe esaercni ot noitalumrof dna nemiger evorpmIdnats - tnemtaert enola

enummi htiw tnemtaert noitanibmoc fo ytilibarelot dna ycaciffe erolpxEseiduts lacinilc ni srotaludom

eht ecnahne ot redro ni troffe hcraeser evitaroballoc ssalc dlrow a hsilbatsEPAGNI tuoba egdelwonk ´ ,gurd noitanibmoc dna enoladnats a sa noitca fo edom s

eliforp lacigoloib tnereffid a htiw seugolana PAGNI eziretcarahc ot dna

ledom esuom ”telsi namuh“ wen htiw nemiger noitanibmoc fo noitazimitpo gnisoD.wollof ot SU ,ASK , adanaC ni slairt lacinilc 2 esahP etarelecca ot )nosniktA(

nilusxE wen etaulave ot sledom elbarapmoc ni gnisu hcraeser lacinilcerP srotaludom enummi htiw noitanibmoc dna yparehtonom sa dnuopmoc rosseccus

slairt 2 esahP erutuf rof eraperp ot spets hcraeser txen etareleccA

nO desaB dehsilbatsE eB naC tnempoleveD rof htaP raelC A ataD lacinilcerP dna lacinilC yrateirporP elbaliavA

getartS tnempoleveD nilusxE y

Page 6: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

yrevocsiD fo tsiL ehT – ecim DONLI enirum VAA - 01

PLv( eneg nilusniorperp tar VAA - )1LIm gnisserpxe surivonedA -4

nilusnilosoreAsegahporcam cimyht cinegollA

edimareclysotcalaG ahplAahplA - NFIr( norefretni - )ahpla

setycomyht rotpecer llec T ateb/ahplAenidinaugonimA

snegordnAaisehtsenA

113,92 LDM tnadixoitnAANRm DAG esnesitnA

enirpoihtazAitnA - 7B -1

)GCB( nir’euG ettemlaC ellicaBnefolcaB

monev eeBcitsiloiB - LI detaidem -4

II ssalc CHM fo editpep gnikcolBnoitatnalpsnart worram enoB

noitartsaCitnA - 3DCitnA - 4DC

sllec T yrotaluger+52DC+4DCitnA - 8DCitnA - bAM 82DC

tinubus B nixot arelohC - nietorp nilusnifles devired I ssalC -I- 45( )7g(ateb A - editpep )67

erusopxe dloCitnA - rotpecer tnemelpmoc

tnavujda s’dnuerF etelpmoCitnA - ALTC -4

)sEDP( sesaretseidohpsohp editoelcun cilcyCniropsolcyC

A niropsolcyCFN ni tneicifed CD - Bappak

edon hpmyl citaercnap morf CDLI htiw CD -4

trocazalfeDnilaugorepsyxoeD

loidartse/enomroh htworg/enoretsegorp/enosahtemaxeDedixozaiD

0601HK ,3D nimatiV yxordyhid 52,1loreficlacelohcyxordyhid 52,1

3D nimatiV lyxordyhid 52,1erutarepmet detavelE

ytilanoitomE)VMCE( suriv sitidracoymolahpecnE

steid tneicifed dica yttaf laitnessE605KF

)nicoirym( 027YTForetu ni seditpep 56 DAG

itnA - ydobitna lanolconom DAGedimareclysotcalaG

)latanoen( esoculGesalyxobraced dica cimatulG

)laro ,suonevartni ,cimyhtartni ,laenotirepartni(enolc llec 2hT 56 esalyxobraced dica cimatulG

seditpep esalyxobraced dica cimatulG)laro ,suonevartni ,cimyhtartni ,laenotirepartni(

ymotcedanoGedihplusidlyhteonidinauG

56 nietorp kcohs taeH)772p( editpep nietorp kcohs taeH

nilusniorp gnidocne sllec mets citeiopotameHenola gnisuoH

FGI namuH -1I- 45(7g ateb A - editpep )67

itnA -I- seidobitna lanolconom AitnA - MACI -1

seidobitna a2GgInoitazilibommI

edimonIitnA - 4 ahpla nirgetni

)lasan ,suoenatucbus ,laro ,laenotirepartni( nilusnI)dimsalp( niahc B nilusnI

9 sdica onima niahc B/niahc B nilusnI - )lasan ,suoenatucbus ,laro ,laenotirepartni( 32nilusnI - FGI( I rotcaf htworg ekil - )I

itnA - elucelom noisehda ralullecretni - MACI( 1 - )1norefretnI - )laro( ahplanorefretnI - ammag

itnA - norefretni - ammagnorefretnI - nietorp noisuf 1GgI/rotpecer ammagnikuelretnI -1nikuelretnI -4nikuelretnI -4- nietorp noisuf gInikuelretnI -4- dimsalpnikuelretnI - 01nikuelretnI - 01 - AND dimsalpnikuelretnI - 01 - lariv

11 nikuelretnI - namuhnikuelretnI - 21

56 nietorp kcohs taeh lairetcabocym fo noitartsinimda cimyhtartnI772p editpep kcohs taeh lairetcabocym fo noitartsinimda cimyhtartnI

sllec telsI - cimyhtartniL- LEM( nitceleS - )41

)HDL( suriv esanegodyhed etatcaLemosopil rallemalitlum egraL

diorazaLitnA - AFL( negitna detaicossa noitcnuf etycokuel - )1itnA - AFL -1

eniloniuq( edimoniL -3- )edimaxobracedirahccasylopopiL - sllec B detavitca

enillyfosiL)VMCL( suriv sitigninemoirohc etycohpmyL

itnA - mures etycohpmylnoitaniccav etytcohpmyL

suriv sitigninemoirohc citycohpmyLitnA -L- nitceles

nixotohpmyL8ZL

02( 8821CM - ipe - 52,1 - )3D nimativyxordyhid11392 LDM

golana nilusni evitcani yllacilobateMitnA - I ssalc CHMitnA - II ssalc CHM

editpep cilcyc devired II ssalc CHMmsiremihc cienegolla dexiM

saremihc worram enob dexiMetamatulg muidosonoM

)VHM( suriv sititapeh eniruM

muiva muiretcabocyMearpel muiretcabocyM

seidobitna larutaNseidobitnaotua evitcaerylop larutaN

eneg ninoticlac editpeporueN - editpep detaleredimanitociN

enitociNnijniN - neR( ot - nehS - noitalumrof )lanoitidart esenapaJ( opmaK a ,)gnaT

sllec TKNsllec 2.4YN

234KOgnidworcrevO

ymotcetaercnaPenillyfixotneP

negissutreP]C:I[ yloP

teid limitsegerPsserts latanerP

AND nilusniorperPlocuborP

nitcalorPnicymapmaR

DAG gnisserpxe suriv ainiccav tnanibmoceRnietorp geRnietorp geR

marpiloR)noitcejni detaeper( enilaS

inosnam amosotsihcSimeS - NIA ,.g.e( teid deifirup - )67

sserts cinorhc mret trohSaciliS

sumilorcat/sumiloriSetadisuf muidoS

norefretni elbuloS - rotpecer ammagnitatsotamoS

noN - snoitidnoc eerf negohtap cificepssnixotoretne laccocotpertS

nicotozotpertS)edimareclysotcalagoflus’3( editafluS

snegitnarepuSesatumsid edixorepuS - enimaxoirrefsed

itnA - rotpecer llec TFGT - ypareht eneg citamos 1 ateb

editpep 06psh rof cificeps enolc 1hTitnA - yht -1

)latanoen( ymotcemyhTedimatubloT

sdnagil rotpecer D nimativ yb decudni sllec citirdned cinegoreloTkcar eht fo poT

esorcus v/w %01 a htiw denibmoc tnemtaerT - gniknird detnemelppus retaw

rotcaf sisorcen romuT - ahpla91( 725XT - ron - 02,41 - ipesib - 32 - eny - ))3(D)2()HO(52,1E nimatiV

itnA - ALV -4

nilubolgomyhTitnA - 3DC

nidnexE + SLA -4nidnexE + FSL -4nirtsaG + FGE

slleC T yrotalugeRnoitatnalpsnarT telsI

serehpsorciM027YTF

MACIs - )rotceV surivonedA( gI

.tse 1102 ylraE - 004~

4002 fo sa 391=N

adirolF fo ytisrevinU ,nosniktA kraM .rD

modsiW lanoitnevnoCdenrutrevO

eht ni htaed fo yellav eht etagivan nac seirevocsid ynam woH? mgidarap dlo

Page 7: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

ksiR & tcA gnicnalaB

tessAeulaV

yrotalugeR

tnempoleveD lacinilC

ssenisuB

snruteR rotsevnI

laicremmoCsnruteR

yenoM & emiT

• 01 noitazilaicremmoC ot yrevocsiD morf emiT - sraey 02• sraey 5 = sCV rof tixE egarevA• sraey 41 = srotsevnI legnA rof tixE egarevA

Page 8: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

yellaV eht ni segnellahC• ot seirevocsid gnitalsnart fo ksir dna ,tsoc ,emiT

tnacifingis enogrednu evah tnempoleved laicremmoc.sraey 5 tsap eht ni egnahc

• egats ylrae dna yrevocsid gnicruostuo si amrahp giB .ksir etagitim ot troffe na ni tnempoleved

• era gnidnuf dna spihsrentrap fo secruos weN .yrassecen

• elba srotavonni ot snruter taerg sesimorp ksir fo tfihS .senotselim eveihca ylevitceffe tsoc ot

• senotselim eveihca ot stsoc dna senilemit gnicudeRwonk seriuqer - .woh

Page 9: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

ot noitareleccA & ygetartS lanoitalsnarThcaeR nihtiW sI COP

• ,ygetarts tcudorp a otni ecneics gnitalsnart yb nevirD ,yawhtap yrotaluger ,txetnoc lacinilc stcelfer hcihw

sehcaorppa gnitepmoc dna• ydutS tpecnoC fo foorP ot htaP tsetrohS eht no sucoF

– lacinilc ,CMC ,lacinilcerP ,yrotalugeR• sksir dna noitcelfni eulav gnidnatsrednu no esaB

ssecorp tnempoleved gurd eht gnirud• ecruoser fo hcaer eht ezimixaM - rotavonni deniartsnoc

seinapmoc• rof secruoser setacolla taht erutcurts ssenisuB

noitaerc eulav & senotselim

Page 10: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

tnempoleveD sezylataC muxeniK rof troppuS lacinilC & yrotalugeR

noitavonnI seinapmoc llamS nac yllufsseccus

yb eulav etaerc dna etavonni —• dna noitucexe rof sdnuf gnitcerid dna gnicruoS

senotselim fo tnemeveihca• tuo ti gnidliub yldipar dna nalp dilos a htiw gnitratS

– ssenisub - yrotaluger - tnempoleved lacinilc• sledom lamina tneiciffus dna yrassecen gnizilitU• eht gnicnavda ni ecnalab thgir eht gnikirtS

ssecorp gnirutcafunam• seiduts lacinilc tpecnoc fo foorp gnitegraT• htap lacitirc eht no yltneiciffe gnitucexE

Page 11: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

tcapmI ezimixaM ot seitinutroppO weNesaesiD cilobateM & ,ytisebO ,setebaiD

,yrotalugeR gnitargetnI lacinilC dna ,tnempoleveD ssenisuB

,eciveD ,gurD elytsefiL ,noitirtuNsnoitanibmoC & noitargetnI

snoitaroballoC cigetartS weN

Page 12: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

& stessA yratnemelpmoC etargetnIhtlaeH erotseR oT sehcaorppA

noitaillaP

noissimeR

noitneverP

eruC

lasreveR

tnerruChcaorppasetebaid ot

nilusxE noitarenegeR

mroftalP

setebaiD& enummI

yrotammalfnIsreifidoM

lanicideM teiD/dooF

scitsongaiDgnirotinoM &

ssertS/esicrexEnoitamrofsnarT

esabataD tneitaP nommoC

Page 13: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

htworG rof egareveL• dna ssenisub cigetarts ot secivres dnapxE

secivres yrosivda gnirentrap• ,pihsredael ,spihsnoitaler muxeniK egarevel ylluF

msilobatem ,ytisebo ,setebaid ni noitatuper dna• no desucof seinapmoc rof secivres yrosivda gnirentraP

esaesid cilobatem rof snoitulos• stessa fo enilepip lautriv egareveL• tnemtsevni tcartta dna daeL• eulav esirpretne dnapxE• rof ygetarts lanoitalsnart etargetnI

noitazilaicremmoc• elytsefiL ,stnemelppuS lanoitirtuN ,eciveD ,gurD

snoitanibmoC & noitargetnI

Page 14: Translational Research & DevelopmentCyclic nucleo tide phos phodi esterases (PDEs) Cyclosp o rin Cyclosp o rin A DC deficie nt in NF - kapp aB DC from pancreatic lymph node DC with

senotseliM & ssergorP gnidnuF• dnuora lliw doog dna spihsnoitaler dliuB

sevitaitini tnatropmi• ,ecneics troppus ot spihsnoitaler egareveL

stnemtsevni ,RP ,snoitarepo ssenisub• si tcudorp ruoy erehw stnemnorivne tuo keeS

tnatropmi yllaicepse

ecneirepxE

ssenisuB legnA stnarG stiderC xaT latipaC erutneV gnirentraP

noitaroballoC secruoseR yporhtnalihP aibarA iduaS tnempoleveD cimonocE yrtsudnI fo teN ediW

sredlohekatS