外科学与免疫学ppt课件

外科学与免疫学Surgery&Immunology,1,基本概念BasicPrinciples,2,免疫:Immune:protectfrompathogens免疫性Immunity:Capacityofdefenseinfection免疫应答Immuneresponse:responseofrecognitionandeliminationantigenicityforeignmaterial免疫学Immunology:Thesciencestudyonthestructure&functionoftheimmunesystemScienceofself-nonselfdiscrimination,概念Concepts,3,天然免疫与获得性免疫AdaptiveandInnateimmunity,天然免疫机体与生具有的抵抗外来病原的防御系统无特异性,包括,InnateimmunityBodydefensescomefrombirthAgainstallkindsofpathogens,NotspecificIncludingbarriersBasicbarrier:skin,mucosaPhysicalbarrier:bodytemp,phPhagocytesInflammation,4,AdaptiveorSpecificImmuneresponseHighlyspecificforaparticularpathogenSpecificMuti-typeRemember/memoryTransferable,获得性免疫应答具有高度病原特异性特异性多样性记忆性可转移性,5,6,免疫应答的三个时相Threephasesofimmuneresponse,Recognition:AgrecognizedbylymphocytesActivation:lymphocytesactivationResponse:LymphocytescoordinateanimmuneresponsethateliminatesthesourceoftheAg,识别相激活相效应相,7,免疫系统ImmuneSystem,OrgansoftheImmuneSystem免疫器官CellsoftheImmuneSystem免疫细胞MoleculeoftheImmuneSystem免疫分子,8,LymphoidTissues,PrimarylymphoidorgansThymusTcellmaturefetalliverBonemarrowSecondarylymphoidorgansandtissuesSpleenlymphnodesandlymphaticsystemMucosa-associatedlymphoidtissue(MALT),BCell,9,CellsoftheInnateImmuneSystem,PhagocytesMononuclearphagocytesPolymorphsNeutrophilsEosinophilsBasophilsandmastcellsPlateletsNaturalkiller(NK)cells,10,CellsoftheAdaptiveImmuneSystem,LymphocytesTcellsTTSuppressorTBcellsAntigen-presentingcells(APCs),11,12,13,14,SurfaceMoleculesExpressedonDC,15,抗原递呈细胞的表面标志,16,TB细胞表面标志的主要差别,17,Moleculesofimmunesys,immunoglobulin/BCRTCRcomplementcytokinesadhesionmoleculesMHC,18,TCR,TheTCRheterodimerformstherecognitionunitofthereceptorCD3complexassociateswiththeandformsoftheTCR,19,MHC,MHCImoleculesconsistofanMHC-encodedheavychainboundto2-microglobalin2-MisessentialforexpressionofMHCImoleculesHeavychain1&2domainsformtheAg-bindinggrooveVariationsinaasequencechangetheshapeofthebindinggrooveMHCIIblindinggrooveaccommodatelongerpeptidesthanclassIPeptidesareheldintheMHCmoleculesbindingcleftbycharacteristicanchorresidues,20,Antigenpresentation抗原递呈,TcellsrecognizepeptidefragmentswhichhavebeenprocessedT细胞识别的是经过加工过的多肽片段InteractionwithAPCisessentialforT-cellactivationAPC-T细胞之间的相互作用是T细胞激活所必须,21,AntigenProcessingandPresentation抗原加工与递呈,AgsareprocessedbeforetheyarepresentedtoTcells抗原递呈给T细胞之前须加工AgsarepartiallydegradedintopeptidebeforebindingtoMHCmolecules抗原在与MHC分子结合之前被降解成抗原肽ClassImoleculesassociatewithendogenouslysynthesizedpeptidesI类分子与内原性合成多肽相关Proteasomesarecytoplasmicorganellesthatdegradecytoplasmicproteins蛋白酶体是胞质细胞器以降解胞内蛋白ClassIImoleculesareloadedwithexogenouspeptidesinanendosomalcompartmentII类分子在包涵体内负载外原性抗原多肽,22,TwopathwaysofproteinAgprocessing&presentation蛋白质抗原加工递呈的两类途径,23,24,MainmoleculesassociatedwithTcellactivation,MHC-Pep-TCRtri-molecularcomplexTCR-CD3complexCD4/CD8co-receptorCD45CD28LFA1/ICAM1,CD2/LFA3,25,26,27,TcellActivation,3signals:recognition,activation,growth3receptor-ligants:Pep-TCR,B7-CD28,IL2-IL2R3results:surfacemoleculesexpression,cytokinessynthesisandsecretion,Tcellcloningformingandamplification,28,29,SpecificSignal&Co-stimulator,TcellActivated&Proliferation,30,Cell-mediatedcytotoxicity,CytotoxicTcellsrecognizeAgpresentedonMHCmoleculesNKcellsreactagainstcellswhichdonotexpressMHC-INKcellsexpresstwomajorclassesofinhibitoryreceptorsforMHCmoleculesCytotoxicityismediatedbycombinationsofdirectcell-cellinteractions,cytokinesandthereleaseofgranuleproteinsLigationofFasorthetype-1TNF-RonthetargetcellleadstotheactivationofcaspasesMyeloidcellsinducedamageintargetsprincipallybythereleaseoftoxicmolecules,31,Mechanismsofcytotoxicity,Cytotoxicityiseffectedbydirectcellularinteraction,cytokinesandgranuleexocytosisCytotoxicTcellsandNKcellsinduceapoptosisintheirtargetsCaspasesmediatecelldeathbyapoptosisCytotoxicitymaybesignalledviaFasoraTNFreceptoronatargetcellGranulesofcytotoxicTcellscontainperforinandgranzymes,32,ImmuneResponse,33,Antibody,NeutralizationComplementdependentcytotoxicity(CDC)IgG,IgMAbdependentcellmediatedcytotoxicity(ADCC)IgG,34,Tcell,Granuleexocytosis:profin,granzymeApoptosis:Fas-FasL,35,NKandM,NK:sameasCTL:Granuleexocytosis,ApoptosisNK&M:ADCCM:directkill:releaselysomalenzymesinhibitDNA,RNA,andPro.synthesis,36,Cytokine,LymphocytesdifferentiationandmaturationEnhancemoleculesexpressiononlymphocytesDirecttoxicityAnti-viruses,37,Immunitytoviruses病毒免疫,Virusesareobligateintracellularparasites病毒是专性胞内寄生物Viruseshaveevolvedstrategiestoavoidrecognitionbythehost病毒通过进化以逃避宿主识别Virusesmaydirectlydisruptthefunctionoftheimmunesystem病毒可以直接破坏免疫系统功能,38,39,Innateimmuneresponsetoviruses天然免疫,Initialdefence:Integrityofthebodysurface初始抵御：机体表面的完整性IFNstimulatesinhibitionofviralreplicationIFN刺激抑制病毒复制NKcellsarecytotoxicforvirallyinfectedcellsNK细胞对被感染细胞的细胞毒作用Macrophagesbecomeactive巨嗜细胞的活化,40,Adaptiveimmuneresponse获得性免疫应答,Antibodyandcomplementcanlimitviralspreadorre-infectionAb和补体限制病毒播散或再感染AntibodycanneutralizetheinfectivityofvirusesAb中和病毒complementsininvolvedintheneutralizationofsomefreeviruses补体中和一些游离病毒Absmobilizecomplement&/oreffectcellstodestroyvirus-infectedcellsAb动员补体和/或效应性细胞杀伤病毒感染的细胞,41,Adaptiveimmuneresponse获得性免疫应答,TcellmediateviralimmunityinseveralwaysT细胞介导的抗病毒免疫MostoftheAbresponseisthymusdependent,requiringthepresenceofCD4+Tcellsforclassswitchingandaffinitymaturation.抗体应答须要有CD4+T的辅助CD4+TcellsalsohelpintheinductionofCD8+CTLCD4+T还可以辅助诱导CD8+CTLCD4+TintherecruitmentandactivationofmacrophagesatsitesofvirusinfectionCD4+T在病毒感染部位可募集和激活巨嗜细胞CD8+Tcellsarealsoeffectiveinpreventionofre-infection.CD8+T可有效地防止再感染,42,43,TumorImmunology,44,Immunesurveillance免疫监视,Immunesurveillanceisaconceptthatenvisagespreventionofthedevelopmentofmosttumorsthroughearlydestructionofabnormalcellsbythehostsimmunesys机体免疫系统可以发挥免疫监视作用，识别并消灭任何表达新抗原的“异己”成分或突变细胞，以保持机体内环境的稳定Surveillanceismosteffectiveagainstvirusesnottumorcells,45,Immunesurveillance免疫监视的证据,Postmortemdatasuggestthattheremaybemoretumorsthanbecomeclinicallyapparent尸检资料显示肿瘤实际发生率高于临床发现Manytumorscontainlymphoidinfiltratesandinsometumorsthismaybefavorablesign许多肿瘤有淋巴细胞浸润，在某些肿瘤是预后好的征象Spontaneousregressionoftumoroccurred有肿瘤自行消退的现象Tumorsoccurredmorefrequentlyintheneonatalperiodandinoldage,whentheimmunesysfunctionslesseffectively免疫功能低下状态肿瘤更易发生Tumorsarisefrequentlyinimmunosuppressedindividuals免疫抑制状态肿瘤发生率高,46,CauseofcommontumourvirusesinvolvedimmunodeficiencytypesInheritedlymphomaEBVimmunodeficiencylymphomaEBVcervicalcancerpapillomavirusesimmunosuppressionskincancerprobablyfororgantransplantspapillomaorduetoAIDSviruseslivercancerhepatitisBandCvirusesKaposishumanherpessarcomavirus8malariaBurkittsEBVlymphomaautoimmunitylymphomaEBV,Tumourvirusesandimmunodeficiency,47,TumourOrganismAdultT-cellleukaemiaHumanTleukaemiavirusI(HTLVI)BurkittslymphomaandEBVLymphomainimmunosuppressionCervicalcancerHumanpapillomaviruses(HPV16and18andothers)LivercancerHepatitisBandCNasopharyngealcancerEBVSkincancerProbablyhumanpapillomavirusesStomachcancerHelicobacterpylori,Micro-organismsandhumantumours,48,Tumorantigens-Classification,ClassIHLA-restrictedcancer/testisAgsClassIHLA-restricteddifferentiationAgsClassIHLA-restrictedwidelyexpressedAgsClassIHLA-restrictedtumorspecificAgsClassIIHLA-restrictedtumorAgsFusionproteins,49,Tumorantigens肿瘤抗原特性,TumorAgsmaybedetectedbyimmunecellsorAbs肿瘤抗原可被T细胞或抗体所检测SharedtumorAgsareviralorigin肿瘤共有抗原通常为病毒原性TumorspecifictransplantationAgsareduetoalterationsintumorgenesorgeneexpression肿瘤特异性抗原通常是肿瘤基因改变后表达产物,50,Antigenname(s)TumourtypesNormaltissuedistributionCancer/testisAgsMAGE1SomemelanomasTestisMAGE3andothertumourBAGEtypesGAGEMelanocytediffAgsMelanA/MART-1MelanomaNormalTyrosinasemelanocytesgp100/Pmel17gp75/TRP-1DiffAgsofotherPSAProstateProstateCEAColonandotherColoncarcinomasMutatedAgsMutatedrasManycarcinomasNotpresentHer-2/neuBreastandovaryNotpresent,Humantumour-associatedantigensrecognizedbyTlymphocytes,51,52,53,NameSourcecDNAlibraryCancertestisAgsHOM-Mel-40MelanomaNY-ESO-1MelanomaMAGE1MelanomaDiffAgsTyrosinaseMelanomaGalectin-9HodgkinsdiseaseCarbonicanhydraseRenalcarcinomaHousekeepinggenesPCNAMelanomaEndogenousretroviralgenesMelanomaHERV-K10MutatedAgsp53(mutated)Coloncarcinoma,AntigensidentifiedbySEREX（SerologicalanalysisofrecombinantcDNAexpressionlibraries）,54,SerologicalanalysisofrecombinantcDNAexpressionlibraries（SEREX）,55,56,57,Activenon-specificBCG,Corynebacteriumparvum,levamisole,cytokinesspecificTherapeuticvaccinesoftumourcells,cellextracts,purifiedorrecombinantantigens,peptides,heatshockproteinsorDNAantigen-pulseddendriticcellsPassivenon-specificLAKcellsspecificAntibodiesaloneorcoupledtoddrugs,pro-drugs,toxinsorradioiisotope,bi-specificantibodiesTcellsCombinedLAKcellsandbi-specificantibody,Immunotherapyoftumours,58,Immunotherapy免疫治疗策略,ImmunizationwithtumorAgs肿瘤抗原免疫Immunizationwithdendriticcells树突状细胞免疫Non-specificstimulationofimmuneresponses非特异性免疫Immunotherapywithcytokinecancausetumorregression细胞因子免疫治疗Immunizationwithoncogenicviruses肿瘤性病毒,59,PassiveImmunotherapy过继性免疫治疗,TherapywithLAKcellsImmunotherapywithTcellsTherapywithantibodies,60,DC免疫治疗,61,TumourTargetantigenImmunizationBreastMUC1SialylTNAg-KLHconjugatewithadjuvantRecombinantVaccinia-MUC1viruswithIL-2CervixHPVE6/E7RecombinantVacciniaHPVE6/E7RecombinantE6/E7proteinSyntheticpeptidesinadjuvantLymphomaIgRecombinantproteinidiotypeldiotypesinglechainFv-toxoidDNAconstructDCpulsedwithidiotypicproteinMelanomaVariousAllogeneicwholecells,cellstrasducedwithCK,Peptides,DC/peptidesorDC/tumorlysateProstatePSALiposomeencapsulatedPSA,DC/peptidesGloboHSyntheticAg-KLHconjugatewithQS21hexasaccharideadjuvant,Clinicaltrialsofactiveimmunizationinman,62,TypeofBRMexamplesmajoreffectbacterialproductsBCG,C.parvum,activateMNKmuramyldipeptidetrehalosedimycolateSyntheticpyrancopolymer,induceIFNprod.moleculesMVE,polyI:C,pyrimidinesCytokinesIFN，activateMNKIL-2,TNFHormonesthymosin,thymulin,modulatethymopoietinT-cellfunctioin,Non-specficactiveimmunotherapy:biologicalresponsemodifiers(BRMs),63,Cytokinetumourtypecytokineeffectsandpossibleandresultsanti-tumourmechanismsIFNprolongedremissionspossiblecytostaticofhairy-cellleukaemiaeffectontumourweakeffectsonincreasedexpressionofsomecarcinomasMHCclassI,cytostasisIFNineffectivesystemically,increasedMHCclassIandIIremissionsofperitonealmacrophageactivationcarcinomaoftheovaryTcactivation,cytostasisIL-2remissionsinrenalT-cellactivationcancerandmelanomaandproliferationNK-cellactivationTNFcanreduce?increasedtumourmalignantascitescelladhesion,macrophageandlymphocyteactivation,Cytokinetherapyfortmours,64,65,66,67,68,肿瘤共刺激分子丢失,69,肿瘤细胞MHC分子表达缺失,70,肿瘤逃避免疫识别的机制,71,ObstaclestotumorimmunitySelf-originoftumorantigensMostproteinsthatareexpressedbytumorcellsarerecognizedbytheimmunesystemasself-antigens.Theestablishmentoftumorimmunitycanthereforebeconstruedasanattempttoinduceautoimmunity.Immunemechanismsthathaveevolvedtoavoidautoimmunity,suchasimmunologicalignorance,clonaldeletionandanergy,thereforehampertheantitumorresponseAntigenlossTumorcellscandown-regulatetheexpressionofantigensthatarerecognizedbytheimmunesystem.Thisabilitytoimmuno-edittumorantigenprofilesunderscorestheimportanceofdirectingTcellsagainstmultipletumorantigens.Down-regulationofHLAexpressionTumorcellscanalsodown-regulatetheexpressionofHLAclassIResistancetoCTLsTcellsexpresscytolyticandapoptosis-inducingmoleculessuchasFASL,TNF-,perforinandgranzyme.Tumouscandown-regulatethereceptorsorthedownstreamsignalsthatareactivatedbythesemoleculestoevadeCTLinducedcelldeathEnvironmentalsuppressionTumorsmightsecreteorexpressmoleculesontheircellsurfacethatinhibittheimmuneresponseandeventuallyimpairsignalinginTcells,72,TheFRESHcriteriaforexpandingantitumorTcellsFunctionThepreservationofantigenspecificityandcytolyticactivitymustbeenforcedthroughoutexpansion.Thiscanrequireoptimizedantigenpresentationand/orT-cellpurification.RemanenceThegenerationoflong-lastingimmunologicalmemoryisanimportantaspectofcancerimmunotherapy.ThedevelopmentofT-cellmemorycellsrequiressuccessfulT-cellengraftmentandstimulation.ExpansionT-cellnumberisacrucialparameterinexperimentalandclinicalmodelsofadoptivecelltherapy.Therapeuticcelldosesmightexceed109Tcells/kg.ProlongedT-cellculture,carriestheriskofalteringantigenspecificityanddiminishingT-cellfunctionality.SurvivalTcellsshouldbeexpandedinsuchawayastoavoidpassivecelldeath,aswellasactivation-inducedcelldeath,followingtheirinfusionintotherecipient.InvivocytokinesupportandT-cellactivationconditionsduringexvivoT-cellexpansionarecrucialindeterminingthesurvivalofadoptivelytransferredTcells.HomingTcellsshouldhavethecapacitytohometothetumoraprocessthatiscontrolledbytheexpr