HMGB在早期胰島移植物丟失中的作用醫(yī)學(xué)課件

HMGB在早期胰島移植物丟失中的作用HMGB在早期胰島移植物丟失中的作用第1頁●majorobstaclefacingislettransplantationandhampersitsclinicalapplication:earlylossoftransplantedislets→thelowefficiencyofislettransplantation●loss?of?transplanted?islets?iscaused?by?NKT?cell–dependent?IFN-γ?production?by?Gr-1+CD11b+?cells●?in?the?activation?of?NKT?cells?and?Gr-1+CD11b+?cells?in?the?early?loss?of?transplanted?islets?remains?to?be?solved.upstream?eventsBackgroundHMGB在早期胰島移植物丟失中的作用第2頁High-mobility?group?box?1(HMGB1)protein:?DNA-binding?protein?present?in?almost?all?eukaryotic?cells.HMGB1stabilizes?nucleosome?formation?and?acts?as?a?nuclear?factor?that?enhances?transcription?HMGB1play?crucial?roles?in?response?to?tissue?damage,issecreted?by?activated?immune?cells,?including?macrophages,?DCs,?and?NK?cellsHMGB1?inducesinflammatory?responses?by?transduction?of?cellular?signals?through?its?receptors,?such?as?TLR2,?TLR4and?receptor?for?advanced?glycation?end?products?(RAGE)BackgroundHuanYangandKevinJ.Traceya.TargetingHMGB1ininflammation.BiochimicaetBiophysicaActa(BBA)-GeneRegulatoryMechanisms.Volume1799,Issues1-2,January-February,Pages149-156HMGB在早期胰島移植物丟失中的作用第3頁

InvolvementofHMGB1inearlylossoftransplantedisletsSTZ-induced?diabetic?mice?received?200?islets?together?withantibody?once?at?the?time?of?islettransplantation

MethodsandResultsNonfastingplasmaglucoselevelsinSTZ-induceddiabeticmicereceivedisletstransplantationanddifferenttreatmentHMGB在早期胰島移植物丟失中的作用第4頁IFN-γproductionofNKTcellsandGr-1+CD11b+

cellsintheliverreceivingisletsisinhibitedbyanti-HMGB1antibodyFACSprofilesofliverMNCsfromnaivemice,STZ-induceddiabeticmicethatreceived200syngenicislets(IsletTx),andislettransplantedmicetreatedwithanti-HMGB1antibodyorwithchickenIgG.HMGB在早期胰島移植物丟失中的作用第5頁NKTcell–dependentIFN-γproductionbyGr-1+CD11b+cellsuponstimulationwithHMGB1.FACSprofilesofNKTcellsandGr-1+CD11b+cellsafterHMGB1treatment.HMGB在早期胰島移植物丟失中的作用第6頁InvolvementofTLR2andRAGEbutnotTLR4inHMGB1-dependent

earlylossoftransplantedislets.InvitrocytokineproductionbyliverMNCs.NonfastingplasmaglucoselevelsofSTZ-induceddiabeticwild-type,Tlr2–/–,Tlr4–/–,orRage–/–micethatreceived200syngeneicislets.HMGB在早期胰島移植物丟失中的作用第7頁P(yáng)ancreaticisletcellsareamajorsourceofHMGB1,whichmediates

IFN-γproductionbyNKTcellsandGr-1+CD11b+cells.?HMGB在早期胰島移植物丟失中的作用第8頁CelltypesresponsibleforHMGB1-mediatedcytokineproduction.NKTcell–dependentIL-12andIFN-γproductionbyliverMNCsinresponsetoHMGB1.(A)LiverMNCsisolatedfromwild-typeorJα18–/–micewereculturedwithHMGB1invitrofor48hoursandmeasuredforIL-12andIFN-γ.(B)PCRanalysisonHMGB1receptors.(C)CytokineproductioninFACS-sortedliverMNCsuponstimulationwithHMGB1.(D)CytokineproductionbyDCs,Mo/Mφ,orNeuinthepresenceofNKTcells.(E)IntracellularcytokinestainingofliverMNCsafterHMGB1treatment.HMGB在早期胰島移植物丟失中的作用第9頁InvolvementofCD40-CD40LinteractioninproductionofIL-12andIFN-γinearlylossoftransplantedislets.

(A)CD40expressioninDCsandNeubeforeoraftertreatmentwithHMGB1.(B)RequirementofCD40-CD40LinteractionintheproductionofIL-12andIFN-γinthepresenceofNKTcells.(C)NonfastingplasmaglucoselevelsofSTZ-induceddiabeticmicethathadreceived200syngeneicisletsandweretreateddifferently.HMGB在早期胰島移植物丟失中的作用第10頁Thus,?it?is?likely?that?the?first?target?for?HMGB1?is?DCs,?which?in?turn?activate?NKT?cells.?Then,?activated?NKT?cells?themselves?produce?IFN-γ?and?alsostimulate?Neu?to?produce?IFN-γ,?which?is?an?essential?component?of?HMGB1-mediated?early?loss?of?transplanted?islets.Discussion(DCs、?Mo/Mφ,?and?Neu)NKTIFN-γactivated?NeutoproduceIFN-γHMGB在早期胰島移植物丟失中的作用第11頁Islet?cells?themselves?are?a?major?source?of?HMGB1,?which?is?released?from?transplanted?islets.?Since?the?plasma?levels?of?HMGB1?reflect?the?degree?of?islet?damage,?HMGB1?could?be?a?marker?to?predict?rejection?of?transplanted?islets.?HMGB1?stimulates?production?of?inflammatory?cytokines?including?IL-12?and?IFN-γ?in?concert?with?DCs,?NKT?cells,?and?Neu?in?the?liver?receiving?islets.?These?inflammatory?cytokines?accelerated?the?injuries?of?transplanted?islets.?Thus,?a?vicious?cycle?harmful?to?transplanted?islets?is?now?unveiled.?Therefore,?each?pathway?involved?in?the?early?loss?of?transplanted