外科学与免疫学讲义

外科学与免疫学

Surgery&Immunology

基本概念

BasicPrinciples

概念Concepts

免疫：Immune:免除传染protectfrompathogens

免疫性Immunity:抗感染的能力Capacityofdefenseinfection

免疫应答Immuneresponse:responseofrecognitionandeliminationantigenicityforeign

material

免疫学Immunology:Thesciencestudyonthestructure&functionoftheimmunesystem

Scienceofself-nonselfdiscrimination

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Includingbarriers,Basicbarrier:skin,mucosa.Physicalbarrier:bodytemp,ph

Phagocytes，Inflammation

AdaptiveorSpecificImmuneresponse

Highlyspecificforaparticularpathogen

Specific

Muti-type

Remember/memory

Transferable

免疫应答的三个时相Threephasesofimmuneresponse

Recognition:Agrecognizedbylymphocytes

Activation:lymphocytesactivation

Response:LymphocytescoordinateanimmuneresponsethateliminatesthesourceoftheAg

免疫系统ImmuneSystem

OrgansoftheImmuneSystem免疫器官

CellsoftheImmuneSystem免疫细胞

MoleculeoftheImmuneSystem免疫分子

LymphoidTissues

Primarylymphoidorgans

Thymus------Tcellmature

fetalliver

Bonemarrow

Secondarylymphoidorgansandtissues

Spleen

lymphnodesandlymphaticsystem

Mucosa-associatedlymphoidtissue(MALT)

CellsoftheInnateImmuneSystem

Phagocytes

Mononuclearphagocytes

Polymorphs

Neutrophils

Eosinophils

Basophilsandmastcells

Platelets

Naturalkiller(NK)cells

CellsoftheAdaptiveImmuneSystem

Lymphocytes

Tcells,a3TY5TSuppressorT

Bcells

Antigen-presentingcells(APCs)

Moleculesofimmunesys

immunoglobulin/BCR

TCR

complement

cytokines

adhesionmolecules

MHC

TCR

TheaBTCRheterodimerformstherecognitionunitofthereceptor

CD3complexassociateswiththeapandY5formsoftheTCR

MHC

MHCImoleculesconsistofanMHC-encodedheavychainboundtoB2-microglobalin

B2-MisessentialforexpressionofMHCImolecules

Heavychainax&a2domainsformtheAg-bindinggroove

Variationsinaasequencechangetheshapeofthebindinggroove

MHCIIblindinggrooveaccommodatelongerpeptidesthanclassI

PeptidesareheldintheMHCmoleculesbindingcleftbycharacteristicanchorresidues

Antigenpresentation抗原递呈

Tcellsrecognizepeptidefragmentswhichhavebeenprocessed

T细胞识别的是经过加工过的多肽片段

InteractionwithAPCisessentialforT-cellactivation

APC-T细胞之间的相互作用是T细胞激活所必须

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

ClassImoleculesassociatewithendogenouslysynthesizedpeptides

I类分子与内原性合成多肽相关

Proteasomesarecytoplasmicorganellesthatdegradecytoplasmicproteins

蛋白酶体是胞质匈胞器以降解胞内蛋白

ClassIImoleculesareloadedwithexogenouspeptidesinanendosomalcompartment

II类分子在包涵体内负载外原性抗原多肽

TwopathwaysofproteinAgprocessing&presentation蛋白质抗原加工递呈的两类途径

AgTypeExampleEnzymesMHCSiteCellPathway

ExogenousBacteriaEndosomeIILysomeCD4+Endocytosis

内原性细菌包涵体溶酶体胞吞

EndogenousVirusesPeoteasomeIERCD8+Cytosolic

外原性病毒蛋白酶体内质网丽质溶解

MainmoleculesassociatedwithTcellactivation

MHC-Pep-TCRtri-molecularcomplex

TCR-CD3complex

CD4/CD8co-receptor

CD45

CD28

LFA1/ICAM1,CD2/LFA3

TcellActivation

3signals:recognition,activation,growth

3receptor-ligants:Pep-TCR,B7-CD28,IL2-IL2R

3results:surfacemoleculesexpression,cytokinessynthesisandsecretion,

TcellcloningformingandampliHcation

Cell-mediatedcytotoxicity

CytotoxicTcellsrecognizeAgpresentedonMHCmolecules

NKcellsreactagainstcellswhichdonotexpressMHC-I

NKcellsexpresstwomajorclassesofinhibitoryreceptorsforMHCmolecules

Cytotoxicityismediatedbycombinationsofdirectcell-cellinteractions,cytokinesandthe

releaseofgranuleproteins

LigationofFasorthetype-1TNF-Ronthetargetcellleadstotheactivationofcaspases

Myeloidcellsinducedamageintargetsprincipallybythereleaseoftoxicmolecules

Mechanismsofcytotoxicity

Cytotoxicityiseffectedbydirectcellularinteraction,cytokinesandgranuleexocytosis

CytotoxicTcellsandNKcellsinduceapoptosisintheirtargets

Caspasesmediatecelldeathbyapoptosis

CytotoxicitymaybesignalledviaFasoraTNFreceptoronatargetcell

GranulesofcytotoxicTcellscontainperforinandgranzymes

ImmuneResponse

Antibody

Neutralization

Complementdependentcytotoxicity(CDC)IgQIgM

Abdependentcellmediatedcytotoxicity(ADCC)IgG

Tcell

Granuleexocytosis:profin,granzyme

Apoptosis:Fas-FasL,

NKandM6

NK:sameasCTL:Granuleexocytosis,Apoptosis

NK&M:ADCC

M6:directkill:releaselysomalenzymes

inhibitDNA,RNA,andPro.synthesis

Cytokine

Lymphocytesdifferentiationandmaturation

Enhancemoleculesexpressiononlymphocytes

Directtoxicity

Anti-viruses

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

Innateimmuneresponsetoviruses

天然免疫

Initialdefence:Integrityofthebodysurface

初始抵御：机体表面的完整性

IFNstimulatesinhibitionofviralreplication

IFN刺激抑制病毒复制

NKcellsarecytotoxicforvirallyinfectedcells

NK细胞对被麻染细胞的细胞毒作用

Macrophagesbecomeactive

巨嗜细胞的活化

Adaptiveimmuneresponse获得性免疫应答

Antibodyandcomplementcanlimitviralspreadorre-infectionAb和补体限制病毒播散或再感

染

Antibodycanneutralizetheinfectivityofviruses

Ab中和病毒

complementsininvolvedintheneutralizationofsomefreeviruses

补体中和一些游离病毒

Absmobilizecomplement&/oreffectcellstodestroyvirus-infectedcells

Ab动员补体和/或效应性细胞杀伤病毒感染的细胞"

Adaptiveimmuneresponse

获得性免疫应答

Tcellmediateviralimmunityinseveralways

T细胞介导的抗病毒免疫

MostoftheAbresponseisthymusdependent,requiringthepresenceofCD4+Tcellsforclass

switchingandaffinitymaturation.

抗体应答须要有CD4+T的辅助

CD4+TcellsalsohelpintheinductionofCD8+CTL

CD4+T还可以辅助诱导CD8+CTL

CD4+Tintherecruitmentandactivationofmacrophagesatsitesofvirusinfection

CD4+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

TumorImmunology

Immunesurveillance

免疫监视

Immunesurveillanceisaconceptthatenvisagespreventionofthedevelopmentofmosttumors

throughearlvdestructionofabnormalcellsbythehosfsimmunesys

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

Immunesurveillance免疫监视的证据

ostmortemdatasuggestthattheremaybemoretumorsthanbecomeclinicallyapparent

尸检资料显示肿瘤实际发生率高于临床发现

Manytumorscontainlymphoidinfiltratesandinsometumorsthismaybefavorablesign

许多沛瘤有淋巴细胞浸润，在某些肿瘤是预后好的征象

Spontaneousregressionoftumoroccurred

有肿瘤自行消退的现象

Ttimorsoccurredmorefrequentlyintheneonatalperiodandinoldage,whentheimmunesys

functionslesseffectively

免疫功能低下状态肿描更易发生

Tumorsarisefrequentlyinimmunosuppressedindividuals

免疫抑制状态肿瘤发生率高

Tlimorantigens-Classification

ClassIHLA-restrictedcancer/testisAgs

ClassIHLA-restricteddifferentiationAgs

ClassIHLA-restrictedwidelyexpressedAgs

ClassIHLA-restrictedtumorspecificAgs

ClassIIHLA-restrictedtumorAgs

Fusionproteins

Tumorantigens肿瘤抗原特性

TiimorAgsmaybedetectedbyimmunecellsorAbs

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

Antigenname(s)TumourtypesNormaltissue

distribution

Cancer/testisAgs

MAGE1SomemelanomasTestis

MAGE3andothertumour

BAGEtypes

GAGE

MelanocytediffAgs

MelanA/MART-1MelanomaNormal

Tyrosinasemelanocytes

gp100/Pmel17

gp75/TRP-l

DiffAgsofother

PSAProstateProstate

CEAColonandotherColon

carcinomas

MutatedAgs

MutatedrasManycarcinomasNotpresent

Her-2/neuBreastandovaryNotpresent

NameSourcecDNAlibrary

CancertestisAgs

HOM-Mel-40Melanoma

NY-ESO-1Melanoma

MAGE1Melanoma

DifTAgs

TyrosinaseMelanoma

Galectin-9Hodgkin'sdisease

CarbonicanhydraseRenalcarcinoma

Housekeepinggenes

PCNAMelanoma

EndogenousretroviralgenesMelanoma

HERV-K10

MutatedAgs

p53(mutated)Coloncarcinoma

Active

non-specificBCG,Corynebacteriumparvum,

levamisole,cytokines

specificTherapeuticvaccinesoftumourcells,

cellextracts,purifiedorrecombinant

antigens,peptides,heatshockproteins

orDNAantigen-pulseddendriticcells

Passive

non-specificLAKcells

specificAntibodiesaloneorcoupledtoddrugs,

pro-drugs,toxinsorradioiisotope,

bi-specificantibodiesTcells

CombinedLAKcellsandbi-specificantibody

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

PassiveImmunotherapy过继性免疫治疗

TherapywithLAKcells

ImmunotherapywithTcells

Therapywithantibodies

TiimourTargetantigenImmunization

BreastMUC1SialylTNAg-KLHconjugatewithadjuvant

RecombinantVaccinia-MUC1viruswithIL-2

CervixHPVE6/E7RecombinantVacciniaHPVE6/E7

RecombinantE6/E7protein

Syntheticpeptidesinadjuvant

LymphomaIgRecombinantprotein

idiotypeIdiotypesinglechainFv-toxoidDNAconstruct

DCpulsedwithidiotypicprotein

MelanomaVariousAllogeneicwholecells,cellstrasducedwithCK,

Peptides,DC/peptidesorDC/tumorlysate

ProstatePSALiposomeencapsulatedPSA,DC/peptides

GloboHSyntheticAg-KLHconjugatewithQS21

hexasaccharideadjuvant

TypeofBRMexamplesmajoreffect

bacterialproductsBCGC.parvum,activateM小NK

muramyldipeptide

trehalosedimycolate

Syntheticpyrancopolymer,induceIFNprod.

moleculesMVE,polyI:C,

pyrimidines

CytokinesIFNaBY,activateM6NK

IL-2,TNF

Hormonesthymosin,thymulin,modulate

thymopoietinT-cellfunctioin

Cytokinetumourtypecytokineeffectsandpossible

andresultsanti-tumourmechanisms

IFNaprolongedremissionspossiblecytostatic

ofhairy-cellleukaemiaeffectontumour

weakeffectsonincreasedexpressionof

somecarcinomasMHCclassI,cytostasis

IFNTineffectivesystemically,increasedMHCclassIandII

remissionsofperitonealmacrophageactivation

carcinomaoftheovaryTcactivation,cytostasis

IL-2remissionsinrenalT-cellactivation

cancerandmelanomaandproliferation

NK-cellactivation

TNFacanreduce?increasedtumour

malignantascitescelladhesion,

macrophageand

lymphocyteactivation

Obstaclestotumorimmunity

Self-originoftumorantigens

•Mostproteinsthatareexpressedbytumorcellsarerecognizedbytheimmunesystemas

self-antigens.

•Theestablishmentoftumorimmunitycanthereforebeconstruedasanattempttoinduce

autoimmunity.Immunemechanismsthathaveevolvedtoavoidautoimmunity,suchas

immunologicalignorance,clonaldeletionandanergy,thereforehampertheantitumorresponse

Antigenloss

•Tumorcellscandovvn-regulatetheexpressionofantigensthatarerecognizedbytheimmune

system.ThisabilitytoMmmuno-ediftumorantigenprofilesunderscorestheimportanceof

directingTcellsagainstmultipletumorantigens.

Down-regulationofHLAexpression

♦Tumorcellscanalsodown-regulatetheexpressionofHLAclassI

ResistancetoCTLs

•Tcellsexpresscytolyticandapoptosis-inducingmoleculessuchasFASL,TNF-a,perforinand

granzyme.Tumouscandown-regulatethereceptorsorthedownstreamsignalsthatare

activatedbythesemoleculestoevadeCTLinducedcelldeath

Environmentalsuppression

・Tiimorsmightsecreteorexpressmoleculesontheircellsurfacethatinhibittheimmune

responseandeventuallyimpairsignalinginTcells

TheFRESHcriteriaforexpandingantitumorTcells

Function

•Thepreservationofantigenspecificityandcytolyticactivitymustbeenforcedthroughout

expansion.Thiscanrequireoptimizedantigenpresentationand/orT-cellpurification.

Remanence

•Thegenerationoflong-lastingimmunologicalmemoryisanimport