醫(yī)學(xué)免疫學(xué)-免疫耐受(英文)

Immunologicaltolerance

1IntroductionEstablishmentofimmunologicaltoleranceMechanismsofimmunologicaltoleranceSignificanceandclinicalapplicationContents

2IntroductionEstablishmentofimmunologicaltoleranceMechanismsofimmunologicaltoleranceSignificanceandclinicalapplicationContents

3IntroductionAgT/Bactivated—EffectorcellAstateofunresponsivenessSpecificforaparticularantigenTolerogen:4IntroductionToleranceResponse“Yin”and“Yang”homeostasisThemostimportantaspect——selftolerancepreventsthebodyfrommountinganimmuneattackagainstitsowntissues5IntroductionClinicalSignificanceautoimmunediseasestumortransplantationinfection61945:Owen“Experimentofnature”innon-identicalcattletwinsIntroduction-Historicalbackground71949:Burnet&FennerIfinembryoniclifeexpendablecellsfromageneticallydistinctraceareimplantedandestablished,noantibodyresponseshoulddevelopagainsttheforeigncellantigenwhentheanimaltakesonindependentexistence.Introduction-Historicalbackground81953:PeterMedawarNewBornFetusAdultStageAdultStageIntroduction-HistoricalbackgroundGraftrejectionGraftrejectionGraftsurvivalAstrainAstrainAstrain91957:Burnet’sclonalselectiontheorySelf-AgForeignAgSelf-AgProgenitorcellsLymphocyteswithspecificdifferentBCR/TCRduringembryostageEliminationofimmatureself-reactivelymphocyteclonesbyclonaldeletionMatureandna?velymphocyterepertoireAntigenspecificlymphocytecloneexpansion(effectcell)andantigeneliminationIntroduction-Historicalbackground10FrankMacfarlaneBurnetandPeterBrianMedawar

"for

discoveryofacquiredimmunologicaltolerance"Introduction-Historicalbackground11TypesofimmunologicaltoleranceIntroduction-TwotypesoftoleranceCentraltoleranceLymphocytespassthroughastageinwhichtheyencounterself-Agleadingtotoleranceratherthanactivationduringtheirmaturationinthecentrallymphoidorgans.PeripheraltoleranceItisinducedbyrecognitionofantigensduetoinadequatelevelsofthecostimulatorsthatarerequiredforlymphocyteactivation,orbypersistentandrepeatedstimulationbyself-Aginperipheraltissues.12IntroductionEstablishmentofimmunologicaltoleranceMechanismsofimmunologicaltoleranceSignificanceandclinicalapplicationContents

13Establishmentofimmunologicaltolerance(1)Antigen-associatedfactorsLow-zonetoleranceAgoftoolowdosagedoesnotinitiateimmuneresponse.High-zonetoleranceAgofhighdosagedoesnotinitiateimmuneresponse.DOSE?14DifferentfeaturesofT

andB

celltolerance T BToleranceinduction

easy

difficultDoseofAg

low

highPersistenttimelonger

shorterEstablishmentofimmunologicaltolerance(1)Antigen-associatedfactors15DaysafterAgimmunizationImmunologicaltoleranceTcellSpleenBcellsBonemarrowBcellsTheminimumtolerancedose:Bcells,1-10mg;Tcells,10ug16MonomerPhysicalnatureEstablishmentofimmunologicaltoleranceAbAbpolymerTolerance(1)Antigen-associatedfactors17RouteofAdministrationEstablishmentofimmunologicaltolerance(1)Antigen-associatedfactorsOraladministrationmucosalimmunityinlocalsystemictolerance18RouteofAdministrationEstablishmentofimmunologicaltolerance(1)Antigen-associatedfactorsOralIntravenousIntra-peritonealIntramuscularsubcutaneousImmuneresponseTolerance19EstablishmentofimmunologicaltolerancePersistenceofAgAntigenicvariationHIV,HCVstimulatesTcellsapoptosis(1)Antigen-associatedfactors20EstablishmentofimmunologicaltoleranceFactorsaffectingtolerance

roleofantigenFactors

thataffect

response

FavorImmuneresponse

FavorTolerance

Physical

form

of

Ag

Route

of

injection

Dose

of

antigen

Large,

aggregated,complex

molecules,properly

processed

Subcutaneousorintramuscular

Optimal

dose

soluble,aggregate-free,simple

small

molecules,not

processed

Oral

or,sometimes,intravenous

Very

large

or

very

small

dose

21EstablishmentofimmunologicaltoleranceSpeciesStatusofimmunesystemEasyinmurineandratDifficultinhuman(2)Host-associatedfactorsAgePhysicalstatusGeneticbackground22EstablishmentofimmunologicaltoleranceFactorsaffectingtolerance

roleofhostFactors

thataffect

response

FavorImmuneresponse

FavorTolerance

Ageofrespondinganimal

Differentiationstateofcells

Fullydifferentiated;memoryT&Bcells

Older,immunologicallymature

Newborn(mice),immunologicallyimmature

RelativeundifferentiatedBcellwithonlyIgM,Tcellsinthethymiccortex

23IntroductionEstablishmentofimmunologicaltoleranceMechanismsofimmunologicaltoleranceSignificanceandclinicalapplicationContents

24Mechanismsofimmunologicaltolerance(1)CentralTolerance(incomplete)NegativeselectionofT,BcellsincentralimmuneorgansSelf-T、BSelf-AgClonaldeletion25MechanismsofimmunologicaltoleranceClonaldeletion:negativeselectionofTcellsinthethymusSelf-Ag:UbiquitousSelf-AgTissue-specificAg(AIRE)26MechanismsofimmunologicaltoleranceClonaldeletion:DeletionofBcellsinthebonemarrow27Mechanismsofimmunologicaltolerance(2)Peripheraltolerance1)ClonaldeletionSomeself-antigensarepresentathighconcentrationintheperipherallymphoidorgans,andTCRbindtheseantigensinhighaffinity,butAPCsexpressfewornocostimulators.28Mechanismsofimmunologicaltolerance(2)Peripheraltolerance2)ImmunologicalignoranceSomeself-antigensarepresentatlowconcentrationintheperipherallymphoidorgans,andTCRbindtheseantigensinlowaffinity,butAPCsexpressfewornocostimulators.29MechanismsofimmunologicaltoleranceNocostimulators3)Clonalanergy(2)Peripheraltolerance30Mechanismsofimmunologicaltolerance(2)Peripheraltolerance4)RegulatoryTcells31Mechanismsofimmunologicaltolerance(2)Peripheraltolerance4)RegulatoryTcells32Mechanismsofimmunologicaltolerance33Mechanismsofimmunologicaltolerance(2)PeripheraltoleranceCharacteristicsnTregiTregInduction

siteThymusPeripheryCD25

expression+++-/+Foxp3++++Ag-specificAuto-Ag(thymus)Tissue-specificAgandforeignAgeffectCell-cellcontact,cytokineproductionCytokine

dependentfunctionInhibition

of

auto-reactive

T

cell

immune

responseInhibitionofauto-reactiveinflammationandgraftrejection,benefitforcancer34Mechanismsofimmunologicaltolerance(2)Peripheraltolerance5)Cytokine35Mechanismsofimmunologicaltolerance(2)Peripheraltolerance6)Signaltransductiondeficiencynegativesignal:PD-1CTLA-4Synthesisinhibited36Mechanismsofimmunologicaltolerance(2)Peripheraltolerance7)ImmunologicallyprivilegedsitesAnatomicbarrierActionofSuppressorlymphocyte(Ts)Actionofcytokines:TGF-β,IL-10ExpressionofFasLapoptosisBrainEyesPlacentaTesticles3738IntroductionEstablishmentofimmunologicaltoleranceMechanismsofimmunologicaltoleranceSignificanceandclinicalapplicationContents

39AutoimmunediseaseOrgantransplantationChronicinfectionTumorInduceBreakupImmunotoleranceSignificance