HMGB在早期胰岛移植物丢失中的作用医学课件

HMGB在早期胰岛移植物丢失中的作用HMGB在早期胰岛移植物丢失中的作用第1页●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在早期胰岛移植物丢失中的作用第2页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在早期胰岛移植物丢失中的作用第3页

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

MethodsandResultsNonfastingplasmaglucoselevelsinSTZ-induceddiabeticmicereceivedisletstransplantationanddifferenttreatmentHMGB在早期胰岛移植物丢失中的作用第4页IFN-γproductionofNKTcellsandGr-1+CD11b+

cellsintheliverreceivingisletsisinhibitedbyanti-HMGB1antibodyFACSprofilesofliverMNCsfromnaivemice,STZ-induceddiabeticmicethatreceived200syngenicislets(IsletTx),andislettransplantedmicetreatedwithanti-HMGB1antibodyorwithchickenIgG.HMGB在早期胰岛移植物丢失中的作用第5页NKTcell–dependentIFN-γproductionbyGr-1+CD11b+cellsuponstimulationwithHMGB1.FACSprofilesofNKTcellsandGr-1+CD11b+cellsafterHMGB1treatment.HMGB在早期胰岛移植物丢失中的作用第6页InvolvementofTLR2andRAGEbutnotTLR4inHMGB1-dependent

earlylossoftransplantedislets.InvitrocytokineproductionbyliverMNCs.NonfastingplasmaglucoselevelsofSTZ-induceddiabeticwild-type,Tlr2–/–,Tlr4–/–,orRage–/–micethatreceived200syngeneicislets.HMGB在早期胰岛移植物丢失中的作用第7页PancreaticisletcellsareamajorsourceofHMGB1,whichmediates

IFN-γproductionbyNKTcellsandGr-1+CD11b+cells. HMGB在早期胰岛移植物丢失中的作用第8页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在早期胰岛移植物丢失中的作用第9页InvolvementofCD40-CD40LinteractioninproductionofIL-12andIFN-γinearlylossoftransplantedislets.

(A)CD40expressioninDCsandNeubeforeoraftertreatmentwithHMGB1.(B)RequirementofCD40-CD40LinteractionintheproductionofIL-12andIFN-γinthepresenceofNKTcells.(C)NonfastingplasmaglucoselevelsofSTZ-induceddiabeticmicethathadreceived200syngeneicisletsandweretreateddifferently.HMGB在早期胰岛移植物丢失中的作用第10页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在早期胰岛移植物丢失中的作用第11页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