慢性移植物抗宿主病

ChronicGVHD:Pathophysiology

andNovelTherapeuticStrategiesTingLiuDepartmentofHematologyWestChinaHospitalSichuanUniversity2021.4.Xiamen.內(nèi)容

UpdateofknowledgesincGVHDProgressinpathophysiologyofcGVHDTreatmentforcGVHDNoveltherapeuticstrategiesofcGVHD.CIBMTR:GVHD發(fā)病率MatchedSiblingMatchedUnrelatedN=3158N=941AcuteGVHDGrade:II18%31%III-IV16%21%ChronicGVHD42%49%RingdénO,etal.Blood.2021;113:3110-3118..NIH新的GVHD分類標(biāo)準(zhǔn)(2005)AcuteGVHDclassicacuteGVHDlate-onsetacuteGVHDChronicGHVDClassicchronicGVHDOverlapsyndromeNIH分類標(biāo)準(zhǔn)最重要的變化是以臨床表現(xiàn)和器官受累的程度，而不是移植后時(shí)間來(lái)進(jìn)行分類，這有利于臨床醫(yī)生作出更符合病理生理學(xué)改變的診斷和治療策略FilipovichAH,etal.

Biol.BloodMarrowTransplant.11(12),945–956(2005)..GVHDclassificationaftertheNIHconsensusconference

PavleticSZ,andFowlerDHHematology2021;2021:251-264.cGVHD發(fā)病的危險(xiǎn)因素AcuteGVHDOlderageofrecipientanddonorFemalemultiparousdonorMismatchedandunrelateddonorsPBSCproductDiseasetype:CML,Aplasticanemia↓HighCD34doseand/orT-celldoseSecondtransplantsDLIsCMV?.影響cGVHD發(fā)病率的因素ClassificationProgressivepoorestprognosisQuiescentdenovo#1riskfactor:historyofacuteGVHDChangingriskfactorsOlderrecipientageDonors(unrelated,haploidentic)Non-myeloablativeconditioningPeripheralbloodstemcellsourceDonorleukocyteinfusions(DLI)Leeetal.,BiolBloodMarrowTransplant2003;9:215-33..慢性GVHD的臨床表現(xiàn)受累器官系統(tǒng)肯定為慢性GVHD的臨床表現(xiàn)可能為慢性GVHD的臨床表現(xiàn)皮膚硬皮病，扁平苔蘚，白癜風(fēng)，疤痕性脫發(fā)，毛發(fā)角化過(guò)度，皮膚攣縮，甲床發(fā)育異常濕疹樣皮疹,皮膚干燥,斑丘疹,脫發(fā),色素沉著黏膜扁平苔蘚，口干癥，非感染性潰瘍，角膜糜爛/非感染性結(jié)膜炎口腔干燥,干燥性角結(jié)膜炎消化道食管狹窄，脂肪瀉食欲減退，吸收不良，體重減輕，腹瀉，腹痛肝臟無(wú)特異性堿性磷酸酶升高,轉(zhuǎn)氨酶增高，膽管炎，高膽紅素血癥泌尿生殖道陰道狹窄，扁平苔蘚非感染性陰道炎，陰道萎縮肌肉骨骼/漿膜非特異性關(guān)節(jié)炎，肌炎，肌無(wú)力，漿膜炎，攣縮性關(guān)節(jié)固定關(guān)節(jié)痛血液系統(tǒng)無(wú)特異性血小板減少,嗜酸性細(xì)胞增多，自身免疫性血細(xì)胞減少肺閉塞性細(xì)支氣管炎閉塞性細(xì)支氣管炎伴機(jī)化性肺炎，間質(zhì)性肺炎.cGVHD:多形性的皮膚病變EpidermalcGVHDLichenplanus-likePapulosquamousIchthyosiformPoikilodermaKeratosispilaris-likeAcralerythemaDermalcGVHDLichen-sclerosus-likeDermalsclerosisSubcutaneouscGVHDSubcutaneoussclerosisFasciitis.

cGVHD

..cGVHD：口腔黏膜潰瘍TreisterNetal.Blood2021;120:3407-3418.Pérez-SimónJAetal.Haematologica2021;97:1187-1195不同類型cGVHD的預(yù)后.MultivariateriskfactorprofilesacuteGVHDandchronicGVHDFlowersM,etal.Blood.2021;117(11):3214-3219).cGVHD危險(xiǎn)度積分*Mild–nosignificantimpairmentoffunctionOnly1-2organs(exceptlungs)Maximumorganscore1Moderate–significantimpairmentbutnomajordisabilityThreeormoreorganswithmaxscore1Oneorganwithmaxscore2Lungscoreof1Severe–majordisabilityScoreof3inanyorganorsiteLungscoreof2*采用危險(xiǎn)度積分代替了既往局限性和廣泛性的分類.

OS：根據(jù)cGVHD危險(xiǎn)度積分PavleticSZ,andFowlerDHHematology2021;2021:251-264.內(nèi)容

UpdateofknowledgesincGVHDProgressinpathophysiologyofcGVHDTreatmentforcGVHDNoveltherapeuticstrategiesofcGVHD.cGVHD的病理生理學(xué)ThymicdamageanddefectivenegativeselectionDeficiencyofT-regsTGF-βandPDGFpathwaysmediatedfibrosisTh1/Th2/Th17paradigmcytokineDysregulatedB-cellandhumoralimmunityTakanoriTeshima,ASBMT2021The5TenetsofcGVHD.中央免疫耐受：胸腺損害學(xué)說(shuō)..外周免疫耐受：T-regs細(xì)胞缺陷T-regsplayacriticalroleinperipheraltoleranceanddevelopmentofcGVHDCD4+lymphopeniaisakeyfactorinTreghomeostasis,andimpairedreconstitutionofTregscanresultinlossoftoleranceanddevelopmentofcGVHDAdoptivetransferofTregsandregulationtoincreaseTregsareconsideredtobee?ectiveclinicalstrategies.TGF-β和PDGF信號(hào)通路與纖維化cGVHDischaracterizedby?brosticchanges,TGF-β1levelsareincreasedsigni?cantlyinthepatientsTGF-βplaysanimportantroleinthegenerationandmaintenanceofTregsPDGFpathwaymayresultinautoimmunee?ects,andstimulatoryantibodiestothePDGFRwerefoundinallextensivecGVHDpatientsImatinibmayinhibitPDGFR,hasbeeninvestigatedfortherefractorycGVHD.TheTh1/Th2/Th17的發(fā)育和平衡WeaverCT.Immunity.2006;24(6):677-88..TheTh1/Th2/Th17發(fā)育和平衡DonorCD4+Tcellscanreciprocallydi?erentiateintoTh1,Th2,andTh17cellsThatmediateorganspeci?cGVHD(Th1:gutandliver;Th2:lungandskin;Th17:gutandskin)Th1andTh17contributetothedevelopmentofcGVHD.cGVHD：B細(xì)胞和體液免疫異常AstrongcorrelationbetweencGVHDandthepresenceofantibodiestoYchromosomeencodedhistocompatibilityantigensElevatedBcell-activatingfactor(BAFF)levels,whichpromotessurvivalanddi?erentiationofactivatedBcells,havebeenobservedinpatientswithcGVHD.GeneticvariationinBAFFwasalsocorrelatedwithcGVHDcGVHDwasassociatedwithanincreasednumberofBcellsexpressinghighlevelsofToll-likereceptor9InvivodepletionofBcellsusingrituximabcansuppresstheprogressionofcomplexcGVHD.cGVHDSummaryThymusHSCCD8CD4TregBInflammatorycytokinesFibrosingcytokinesAutoantibodyFibrosisandorgandysfunctionDeathfrominfection/organfailureAlloAuto.內(nèi)容UpdateofknowledgesincGVHDProgressinpathophysiologyofcGVHDTreatmentforcGVHDNoveltherapeuticstrategiesofcGVHD.cGVHD的藥物預(yù)防Seatlegroupobservedextendedcalcineurininhibitor(CSA)treatmentmaydecreasechronicGVHDCSA6monthsvs24monthsinpatientswithprioraGVHDorevidenceofsubclinicalchronicGVHDonskinbiopsy=NOEFFECTThalidomideD+80HIGHERrateofcGVHDandmortalitySteroidsuntil6monthsaftertransplantationHIGHERthanexpectedincidenceofseverecGVHDHydroxychloroquine+CSAx1yr=NOEFFECTMMF(D150)+CSA(D80)=NOEFFECTPre-transplantATGmaydecreasecGVHDMangarellietal.Hematologica.2003;88:315, Kansuetal.Blood.2001;98:3868. Chaoetal.BBMT.1996;2:96Ringdenetal.ExpHem.1985;13:1062 Fongetal.BBMT.2007;13:1201 Baronetal.BBMT.2007;13:1041.cGVHD：系統(tǒng)治療指征GlobalseverityHighriskformortality*Systemictreatment

MildNo

NoMildYes

Yes?ModerateNo/YesYesSevereNo/Yes

Yes*Platelets<100,000/microliterorreceivingsteroidsattimeofdiagnosisofCGVHD?Thebenefitsofgraft-vs.-tumoreffectandtheriskofCGVHDneedtobeweighted

Filipovic,BBMT2005;12:945-955.Steroids:Sullivanetal,Blood1988;72.N=164Pred1mg/kgvsPred+AzathioprineNRM21%vs41%(p=0.03)Mostcommoncauseofdeath=relapseSteroids+CSA:Kocetal,Blood2002;100.N=287RCT:PredvsPed+CSANodifferenceinTRM,OS,relapse,needforsecondarycGVHDTxRelapsefreesurvivalbetterinprednisoneonlyarm

cGVHD:一線治療Martin.IntJHem.2004;79:221 Stewartetal,Blood2004;104Vogelsang.BJH.2004;125:435 Lee,Blood.2005;105.ProgressiononsteroidsWithin2-3monthsifnoimprovementonsteroidsInabilitytotapersteroidswithoutrecurrenceInabilitytotoleratesteroidsorcalcineurininhibitors(TTP)cGVHD:二線治療.SteroidpulseCSATacroMMFSirolimusECPPentostatinRituximabHydroxychloroquineThalidomide/RevlimidClofazamineAzathioprineATGTLILowdoseMTXDacluzimabInfliximabEtanerceptImatinibMontelukastcGVHD:二線治療可選擇藥物.cGVHD：二線治療的療效Leeetal,BBMT2002.ResponseratesinsecondlinetherapyNishimoriH,ActaMedOkayama.2021;67(1):1-8..內(nèi)容UpdateofknowledgesincGVHDProgressinpathobiologyofcGVHDTreatmentforcGVHDNoveltherapeuticstrategiesofcGVHD.Keratinocytegrowthfactor(KGF)KGFtreatmentimprovestherestorationofthymicDCsandpreventsthedenovogenerationofpathogenicCD4+TcellscausingcGVHDthee?cacyofpalifermintreatmentforcGVHDhasbeingclinicalstudiestoassesstheroleofthethymusasatargetofcGVHDtreatmentZhangY,JImmunol(2007)179:3305