外科學(xué)與免疫學(xué)

Surgery&Immunology

基本概念

BasicPrinciples

概念Concepts

免疫：Immune:免除傳染protectfrompathogens

免疫性Immunity:抗感染的能力Capacityofdefenseinfection

免疫應(yīng)答Immuneresponse:responseofrecognitionandeliminationantigenicityforeign

material

免疫學(xué)Immunology:Thesciencestudyonthestructure&functionoftheimmunesystem

Scienceofself-nonselfdiscrimination

天然免疫與獲得性免疫

AdaptiveandInnateimmunity

天然免疫

機(jī)體與生具有的抵抗外來病原的防御系統(tǒng)

無特異性，包括Includingbarriers,Basicbarrier:skin,mucosa.Physicalbarrier:bodytemp,ph

Phagocytes，Inflammation

AdaptiveorSpecificImmuneresponse

Highlyspecificforaparticularpathogen

Specific

Muti-type

Remember/memory

Transferable

免疫應(yīng)答的三個(gè)時(shí)相Threephasesofimmuneresponse

Recognition:Agrecognizedbylymphocytes

Activation:lymphocytesactivation

Response:LymphocytescoordinateanimmuneresponsethateliminatesthesourceoftheAg

免疫系統(tǒng)ImmuneSystem

OrgansoftheImmuneSystem免疫器官

CellsoftheImmuneSystem免疫細(xì)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抗原遞呈

Tcellsrecognizepeptidefragmentswhichhavebeenprocessed

T細(xì)胞識別的是經(jīng)過加工過的多肽片段

InteractionwithAPCisessentialforT-cellactivation

APC-T細(xì)胞之間的相互作用是T細(xì)胞激活所必須

AntigenProcessingandPresentation抗原加工與遞呈

AgsareprocessedbeforetheyarepresentedtoTcells

抗原遞呈給T細(xì)胞之前須加工

AgsarepartiallydegradedintopeptidebeforebindingtoMHCmolecules

抗原在與MHC分子結(jié)合之前被降解成抗原肽

ClassImoleculesassociatewithendogenouslysynthesizedpeptides

I類分子與內(nèi)原性合成多肽相關(guān)

Proteasomesarecytoplasmicorganellesthatdegradecytoplasmicproteins

蛋白酶體是胞質(zhì)匈胞器以降解胞內(nèi)蛋白

ClassIImoleculesareloadedwithexogenouspeptidesinanendosomalcompartment

II類分子在包涵體內(nèi)負(fù)載外原性抗原多肽

TwopathwaysofproteinAgprocessing&presentation蛋白質(zhì)抗原加工遞呈的兩類途徑

AgTypeExampleEnzymesMHCSiteCellPathway

ExogenousBacteriaEndosomeIILysomeCD4+Endocytosis

內(nèi)原性細(xì)菌包涵體溶酶體胞吞

EndogenousVirusesPeoteasomeIERCD8+Cytosolic

外原性病毒蛋白酶體內(nèi)質(zhì)網(wǎng)麗質(zhì)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

病毒是專性胞內(nèi)寄生物

Viruseshaveevolvedstrategiestoavoidrecognitionbythehost

病毒通過進(jìn)化以逃避宿主識別

Virusesmaydirectlydisruptthefunctionoftheimmunesystem

病毒可以直接破壞免疫系統(tǒng)功能

Innateimmuneresponsetoviruses

天然免疫

Initialdefence:Integrityofthebodysurface

初始抵御：機(jī)體表面的完整性

IFNstimulatesinhibitionofviralreplication

IFN刺激抑制病毒復(fù)制

NKcellsarecytotoxicforvirallyinfectedcells

NK細(xì)胞對被麻染細(xì)胞的細(xì)胞毒作用

Macrophagesbecomeactive

巨嗜細(xì)胞的活化

Adaptiveimmuneresponse獲得性免疫應(yīng)答

Antibodyandcomplementcanlimitviralspreadorre-infectionAb和補(bǔ)體限制病毒播散或再感

染

Antibodycanneutralizetheinfectivityofviruses

Ab中和病毒

complementsininvolvedintheneutralizationofsomefreeviruses

補(bǔ)體中和一些游離病毒

Absmobilizecomplement&/oreffectcellstodestroyvirus-infectedcells

Ab動員補(bǔ)體和/或效應(yīng)性細(xì)胞殺傷病毒感染的細(xì)胞"

Adaptiveimmuneresponse

獲得性免疫應(yīng)答

Tcellmediateviralimmunityinseveralways

T細(xì)胞介導(dǎo)的抗病毒免疫

MostoftheAbresponseisthymusdependent,requiringthepresenceofCD4+Tcellsforclass

switchingandaffinitymaturation.

抗體應(yīng)答須要有CD4+T的輔助

CD4+TcellsalsohelpintheinductionofCD8+CTL

CD4+T還可以輔助誘導(dǎo)CD8+CTL

CD4+Tintherecruitmentandactivationofmacrophagesatsitesofvirusinfection

CD4+T在病毒感染部位可募集和激活巨嗜細(xì)胞

CD8+Tcellsarealsoeffectiveinpreventionofre-infection.

CD8+T可有效地防止再感染

TumorImmunology

Immunesurveillance

免疫監(jiān)視

Immunesurveillanceisaconceptthatenvisagespreventionofthedevelopmentofmosttumors

throughearlvdestructionofabnormalcellsbythehosfsimmunesys

機(jī)體免疫系統(tǒng)可以發(fā)揮免疫監(jiān)視作用，識別并消滅任何表達(dá)新抗原的“異己”成分或突變細(xì)胞，

以保持機(jī)體內(nèi)環(huán)境的穩(wěn)定

Surveillanceismosteffectiveagainstvirusesnottumorcells

Immunesurveillance免疫監(jiān)視的證據(jù)

ostmortemdatasuggestthattheremaybemoretumorsthanbecomeclinicallyapparent

尸檢資料顯示腫瘤實(shí)際發(fā)生率高于臨床發(fā)現(xiàn)

Manytumorscontainlymphoidinfiltratesandinsometumorsthismaybefavorablesign

許多沛瘤有淋巴細(xì)胞浸潤，在某些腫瘤是預(yù)后好的征象

Spontaneousregressionoftumoroccurred

有腫瘤自行消退的現(xiàn)象

Ttimorsoccurredmorefrequentlyintheneonatalperiodandinoldage,whentheimmunesys

functionslesseffectively

免疫功能低下狀態(tài)腫描更易發(fā)生

Tumorsarisefrequentlyinimmunosuppressedindividuals

免疫抑制狀態(tài)腫瘤發(fā)生率高

Tlimorantigens-Classification

ClassIHLA-restrictedcancer/testisAgs

ClassIHLA-restricteddifferentiationAgs

ClassIHLA-restrictedwidelyexpressedAgs

ClassIHLA-restrictedtumorspecificAgs

ClassIIHLA-restrictedtumorAgs

Fusionproteins

Tumorantigens腫瘤抗原特性

TiimorAgsmaybedetectedbyimmunecellsorAbs

腫瘤抗原可被T細(xì)胞或抗體所檢測

SharedtumorAgsareviralorigin

腫瘤共有抗原通常為病毒原性

TumorspecifictransplantationAgsareduetoalterationsintumorgenesorgeneexpression

腫瘤特異性抗原通常是腫瘤基因改變后表達(dá)產(chǎn)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免疫治療策略

?ImmunizationwithtumorAgs腫瘤抗原免疫

?Immunizationwithdendriticcells樹突狀細(xì)胞免疫

?Non-specificstimulationofimmuneresponses非特異性免疫

?Immunotherapywithcytokinecancausetumorregression細(xì)胞因子免疫治療

?Immunizationwithoncogenicviruses腫瘤性病毒

PassiveImmunotherapy過繼性免疫治療

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