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克罗恩病研究进展流行病学研究概况•发病率分别为4-12/105•近20年来CD增加明显•欧美多见,中国和亚洲国家少见,•青壮年多见,儿童和老年人少见流行病学研究概况亚洲国家克罗恩病发病率在上升国内近15年克罗恩病病例数小计2910•病因、发病机制迄今未明。•主要集中在环境、遗

传和免疫异常等方面。GeneticLinkagesandCDChr.16q12-IBD1NOD26p-IBD3MHCⅠ和Ⅱ14q-IBD4TCRα/β复合体5q-IBD5IL-3,IL-4,IL-519p-IBD6TB4H,C3Others:-

Chr1,2,3,7,XNOD2基因•NOD2/CARD15基因——CD相关基因•Hugot等1996年发现在IBD1位点•仅见于CD而非UC，约20%-30%的CD患者•欧美澳三洲12个研究组613个家庭研究证实•NOD2基因产物是一种细胞内的内毒素结合蛋白,野生型能

清除入侵病原体.•NOD2突变可引起肠道菌群改变导致的免疫激活异常•NOD2突变还可使细胞凋亡机制失常•导致CD慢性炎症和组织破坏•突变杂合子患病危险性增加3倍,纯合子增加23倍.巨噬细胞幼稚的CD4细胞凋亡Th1IFN-γTNFIL

-2延迟超敏反应肉芽肿Th2IL-4IL-5IL-10体液免疫变态反应IL－12IFN-γIL-4克罗恩病的粘膜免疫反应DiseaseMechanisms:ChronicImmuneActivationNaturalHistoryofCrohn’sDisease:ChronicProgressio

nMonoclonalAntibodiesfortheTreatmentofCDEtiologyofCD:ChronicActivationoftheMucosalImmuneResponseEnvironmentalfactorsGeneticfactorsTcellTh1cellTNF-I

L-12IFN-MacrophageInflammationTh1cellTh1cellTh1cellTNF-IFN-IL-12Crohn’sdiseasestateNormalstateChronicuncontrolledinflammat

ionduetoTh1cellapoptoticdefectNormalcontrolledinflammationviaapoptosisofTh1cells(programmedcelldeath)GatelyMKetal.AnnuRevImmunol.1998;16:495-521;InaK

etal.JImmunol.1999;163:1081-1090;PodolskyDK.NEnglJMed.2002;347:417-429CytokineImbalanceinChronicInflammationadaptedfromPapa

christouGetal.PractGastroenterol.2004;28:18-30.KeyInflammatoryMediatorsinCDAntigenAPCcellTcellCD4APCcellActivatedTcellTh1cellTNF-T

NF-ActivatedmacrophageIL-12IFN-GatelyMKetal.AnnuRevImmunol.1998;16:495-521;PodolskyDK.NEnglJMed.2002;347:417-429Interleukin12(IL-12)PromotesTh1

ResponsesinCDAntigenAPCcellTcellCD4APCcellActivatedTcellTh1cellTNF-TNF-ActivatedmacrophageIL-12IFN-GatelyMKetal.A

nnuRevImmunol.1998;16:495-521;PodolskyDK.NEnglJMed.2002;347:417-429RestingmemoryTcellsIL-12IFNTh1cellNaïveTcellsDif

ferentiationGatelyMKetal.AnnuRevImmunol.1998;16:495-521AdditionalMechanismsforIL-12-inducedTh1ReponsesClinicalEvidenceofIncre

asedExpressionofIL-12inCDKakazuTetal.AmJGastroenterol.1999;94:2149-2155.ColpaertSetal.EurCytokineNetw.2002;13:431-437.BerrebiDetal.

AmJPathol.1998;152:667-672.ParronchiPetal.AmJPathol.1997;150:823-832.MonteleoneGetal.Gastroenterology.1997;112:1169-1178.NielsenOHetal.

ScandJGastroenterol.2003;38:180-185.TumorNecrosisFactor(TNF)SustainsTh1ResponsesinCDAntigenAPCcellTcellCD4APCcellAct

ivatedTcellTh1cellTNF-TNF-ActivatedmacrophageIL-12IFN-GatelyMKetal.AnnuRevImmunol.1998;16:495-521;PodolskyDK.NEnglJ

Med.2002;347:417-429TNFPromotesCDActivityandPathogenesisThroughMultiplePathwaysAdaptedfromHoltmannetal.ZGastroenterol.2002;40:587-600.Tissuedestru

ction&inflammationMacrophageTNF-TNF-TNF-IFN-IL-12ActivatedTcellTh1cellCoagulation(increasedproductionofthrombin)Ulcer

InflammationInflammatorycellsClinicalEvidenceofIncreasedExpressionofTNFinCDBraeggerCPal.Lancet.1992;339:89-91.ReineckerHC

etal.ClinExpImmunol.1993;94:174-181MurchSHetal.Gut.1993;34:1705-1709.BreeseEJetal.Gastroenterology.1994;106:1455-1466.M

acDonaldTTetal.ClinExpImmunol.1990;81:301-305.CappelloMetal.Gut.1992;33:1214-1219.CurrentConceptsinCrohn’sDisease(CD)•DiseaseMe

chanisms:ChronicImmuneActivation•NaturalHistoryofCrohn’sDisease:ChronicProgression•MonoclonalAntibodiesfort

heTreatmentofCDTheLikelihoodforDiseaseComplicationsinCDIncreasesOverTimeCosnesJetal.InflammBowelDis.2002;8:244-250.Numberofpatie

ntsatrisk:20025522299537012243648607284961081201321441561681801922042162282400102030405060708090100MonthsCumulati

veprobability%penetratinginflammatorystricturing•Occurrenceofastricturingand/orpenetratingcomplicationwasassessedretrospectivelyin2,002conse

cutiveCDpatients(1974–2000)•TheestimatedrisksforpenetratingCDat5and20yearsafterdiagnosisare40%and70%M

ostPatientsWillProgresstoSurgery•Dataoninitialintestinalresectionandpostoperativerecurrencewereevaluatedretrospectivelyinapopulation-basedcohortof1,

936CDpatients(1955–1989)•Itisestimatedthat75%ofCDpatientswillrequireatleast1intestinalresection•Nearl

y50%ofthesepatientswillhaveaclinicalrelapseBernellOetal.AnnSurg.2000;231:38-45.02468101214020406080100Time(ye

ars)Cumulativeriskofsurgery(%)02468101214020406080100Time(years)Cumulativeriskofrecurrence(%)RiskofFirstR

esectionRiskofRecurrenceAfterFirstResectionTheProportionofPatientsinMedicalRemissionDecreasesOverTimeSilversteinMDetal.Gastroenterolog

y.1999;117:49-57.YearsAfterDiagnosisPostSurgeryRemissionSurgeryDrugRefractoryDrugDependentDrugResponsiveMildRemissionPr

obability010203040506000.10.20.30.40.50.60.70.80.91•MarkovanalysisoftheprojectedlifetimeclinicalcourseofCDinapopulation-basedretrospectivestudyof1

74patients(1970–1993)VelosoFTetal.InflammBowelDis.2001;7:306-313.RemissionWithintheFirstYearofDiagnosisMayPredictFutureDiseaseBehaviorRemissionLowAc

tivityHighActivity0%20%40%60%80%100%012345678910111213141516171819YearsAfterDiagnosis•TheclinicalcourseofCDwasstudiedinacohortof480consecutivepatient

sfollowedfromdiagnosisupto20years(1980–1999)新型生物治疗剂生物治疗剂作用aNF-κB抑制剂或细胞因子单抗抑制IL-12、IL-13bα4β7整合素单抗、趋化因子抑制剂抑制效应细胞移动cTNF特异性抗体抑制TNF表达d调节性T细

胞因子抑制效应性T细胞F选择性黏附分子抑制剂(SAM)抑制免疫细胞向炎症部位聚集RoleforTargetedBiologicTherapyinCrohn’sDisease(CD)•DiseaseMechanisms:ChronicImmuneActivation•Nat

uralHistoryofCrohn’sDisease:ChronicProgression•MonoclonalAntibodiesfortheTreatmentofCDMonoclonalantibodyNosignalCytokine(IL-12orTNF)MonoclonalAn

tibodiesPreventInteractionsofCytokinesWithCellularReceptorsCytokinereceptorChoyEHSetal.NEnglJMed.2001;3

44:907–16.EvolutionofMonoclonalAntibodiesAdalimumab(D2E7)FullyHumanMurineChimericHumanized5–10%MouseProteinHuman(NoMouseProtein)25%MouseProtein100%M

ouseProtein治疗策略TherapeuticPyramidforActiveCrohn’sDiseaseSevereModerateMildSurgeryCorticosteroidsAminosalicylates/AntibioticsImmunomodulatorsInflixim

abInfliximabSurgerySteroidsAZA/6-MP/MTXEarlyReversingtheCrohn’sDiseasePyramid