慢性移植物抗宿主病

Chronic GVHD:Pathophysiology and Novel Therapeutic StrategiesTing LiuDepartment of Hematology West China HospitalSichuan University 2014.4.Xiamen内内 容容 nUpdate of knowledges in cGVHDnProgress in pathophysiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHDCIBMTR:GVHD 发病率发病率Matched SiblingMatched UnrelatedN=3158N=941Acute GVHD Grade:II18%31%III-IV16%21%Chronic GVHD42%49%Ringdn O,et al.Blood.2009;113:3110-3118.NIH 新的新的GVHDGVHD分类标准分类标准(2005)nAcute GVHDclassic acute GVHDlate-onset acute GVHDnChronic GHVDClassic chronic GVHDOverlap syndrome nNIH分类标准最重要的变化是以临床表现和器官受累的程分类标准最重要的变化是以临床表现和器官受累的程度，而不是移植后时间来进行分类，这有利于临床医生作度，而不是移植后时间来进行分类，这有利于临床医生作出更符合病理生理学改变的诊断和治疗策略出更符合病理生理学改变的诊断和治疗策略Filipovich AH,et al.Biol.Blood Marrow Transplant.11(12),945956(2005).GVHD classification after the NIH consensus conference Pavletic S Z,and Fowler D H Hematology 2012;2012:251-264cGVHD发病的危险因素发病的危险因素nAcute GVHDnOlder age of recipient and donornFemale multiparous donornMismatched and unrelated donors nPBSC product nDisease type:CML,Aplastic anemia nHigh CD34 dose and/or T-cell dosenSecond transplantsnDLIsnCMV?影响cGVHD发病率的因素nClassificationnProgressive poorest prognosisnQuiescentnde novon#1 risk factor:history of acute GVHDnChanging risk factorsnOlder recipient agenDonors(unrelated,haploidentic)nNon-myeloablative conditioningnPeripheral blood stem cell sourcenDonor leukocyte infusions(DLI)Lee et al.,Biol Blood Marrow Transplant 2003;9:215-33.慢性慢性GVHD的临床表现的临床表现受累器官系统受累器官系统肯定为慢性肯定为慢性GVHD的临床表现的临床表现可能为慢性可能为慢性GVHD的临床表现的临床表现皮肤皮肤硬硬皮皮病病，扁扁平平苔苔藓藓，白白癜癜风风，疤疤痕痕性性脱脱发发，毛毛发发角角化化过过度度，皮皮肤肤挛挛缩缩，甲甲床发育异常床发育异常湿湿疹疹样样皮皮疹疹,皮皮肤肤干干燥燥,斑斑丘丘疹疹,脱脱发发,色素沉着色素沉着黏膜黏膜扁扁平平苔苔藓藓，口口干干症症，非非感感染染性性溃溃疡疡，角膜糜烂角膜糜烂/非感染性结膜炎非感染性结膜炎口腔干燥口腔干燥,干燥性角结膜炎干燥性角结膜炎消化道消化道食管狭窄，脂肪泻食管狭窄，脂肪泻食食欲欲减减退退，吸吸收收不不良良，体体重重减减轻轻，腹泻，腹痛腹泻，腹痛肝脏肝脏无特异性无特异性碱碱性性磷磷酸酸酶酶升升高高,转转氨氨酶酶增增高高，胆胆管炎，高胆红素血症管炎，高胆红素血症泌尿生殖道泌尿生殖道阴道狭窄，扁平苔藓阴道狭窄，扁平苔藓非感染性阴道炎，阴道萎缩非感染性阴道炎，阴道萎缩肌肉骨骼肌肉骨骼/浆膜浆膜非非特特异异性性关关节节炎炎，肌肌炎炎，肌肌无无力力，浆浆膜炎，挛缩性关节固定膜炎，挛缩性关节固定关节痛关节痛血液系统血液系统无特异性无特异性血血小小板板减减少少,嗜嗜酸酸性性细细胞胞增增多多，自自身免疫性血细胞减少身免疫性血细胞减少肺肺闭塞性细支气管炎闭塞性细支气管炎闭闭塞塞性性细细支支气气管管炎炎伴伴机机化化性性肺肺炎炎，间质性肺炎间质性肺炎cGVHD:多形性的皮肤病变多形性的皮肤病变nEpidermal cGVHDnLichen planus-likenPapulosquamousnIchthyosiform nPoikilodermanKeratosis pilaris-likenAcral erythemanDermal cGVHDnLichen-sclerosus-likenDermal sclerosisnSubcutaneous cGVHDnSubcutaneous sclerosisnFasciitis cGVHDn cGVHD：口腔黏膜溃疡Treister N et al.Blood 2012;120:3407-3418Prez-Simn J A et al.Haematologica 2012;97:1187-1195不同类型不同类型cGVHD的预后的预后Multivariate risk factor profiles acute GVHD and chronic GVHDFlowers M,et al.Blood.2011;117(11):3214-3219)cGVHD危险度积分危险度积分*Mild no significant impairment of function Only 1-2 organs(except lungs)Maximum organ score 1 Moderate significant impairment but no major disabilityThree or more organs with max score 1One organ with max score 2Lung score of 1 Severe major disability Score of 3 in any organ or siteLung score of 2*采用危险度积分代替了既往局限性和广泛性的分类 OS：根据：根据cGVHD危险度积分危险度积分Pavletic S Z,and Fowler D H Hematology 2012;2012:251-264内内 容容 nUpdate of knowledges in cGVHDnProgress in pathophysiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHDcGVHD的病理生理学的病理生理学nThymic damage and defective negative selectionnDeficiency of T-regsnTGF-and PDGF pathways mediated fibrosisnTh1/Th2/Th17 paradigm cytokinenDysregulated B-cell and humoral immunityTakanori Teshima,ASBMT 2008The 5 Tenets of cGVHD中央免疫耐受：胸腺损害学说中央免疫耐受：胸腺损害学说外周免疫耐受：T-regs细胞缺陷nT-regsplayacriticalroleinperipheraltoleranceanddevelopmentofcGVHDnCD4+lymphopeniaisakeyfactorinTreghomeostasis,andimpairedreconstitutionofTregscanresultinlossoftoleranceanddevelopmentofcGVHDnAdoptivetransferofTregsandregulationtoincreaseTregsareconsideredtobeeffectiveclinicalstrategiesTGF-和和 PDGF 信号通路与纤维化信号通路与纤维化ncGVHD is characterized by fibrostic changes,TGF-1 levels are increased significantly in the patientsnTGF-plays an important role in the generation and maintenance of TregsnPDGF pathway may result in autoimmune effects,and stimulatory antibodies to the PDGFR were found in all extensive cGVHD patientsnImatinib may inhibit PDGFR,has been investigated for the refractory cGVHDThe Th1/Th2/Th17 的发育和平衡的发育和平衡Weaver CT.Immunity.2006;24(6):677-88.The Th1/Th2/Th17 发育和平衡发育和平衡nDonor CD4+T cells can reciprocally differentiate into Th1,Th2,and Th17 cellsnThat mediate organ specific GVHD(Th1:gut and liver;Th2:lung and skin;Th17:gut and skin)nTh1 and Th17 contribute to the development of cGVHDcGVHD：B细胞和体液免疫异常细胞和体液免疫异常nAstrongcorrelationbetweencGVHDandthepresenceofantibodiestoYchromosomeencodedhistocompatibilityantigensnElevatedBcell-activatingfactor(BAFF)levels,whichpromotessurvivalanddifferentiationofactivatedBcells,havebeenobservedinpatientswithcGVHD.GeneticvariationinBAFFwasalsocorrelatedwithcGVHDncGVHDwasassociatedwithanincreasednumberofBcellsexpressinghighlevelsofToll-likereceptor9nInvivodepletionofBcellsusingrituximabcansuppresstheprogressionofcomplexcGVHDcGVHD SummaryThymusHSCCD8CD4TregBInflammatory cytokinesFibrosing cytokinesAutoantibodyFibrosis and organ dysfunctionDeath from infection/organ failureAlloAuto内内 容容nUpdate of knowledges in cGVHDnProgress in pathophysiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHDcGVHD的药物预防的药物预防nSeatle group observed extended calcineurin inhibitor(CSA)treatment may decrease chronic GVHDnCSA 6 months vs 24 months in patients with prior aGVHD or evidence of subclinical chronic GVHD on skin biopsy=NO EFFECTnThalidomide D+80 HIGHER rate of cGVHD and mortalitynSteroids until 6 months after transplantation HIGHER than expected incidence of severe cGVHDnHydroxychloroquine+CSA x 1 yr=NO EFFECTnMMF(D150)+CSA(D80)=NO EFFECTnPre-transplant ATG may decrease cGVHDMangarelli et al.Hematologica.2003;88:315,Kansu et al.Blood.2001;98:3868.Chao et al.BBMT.1996;2:96Ringden et al.Exp Hem.1985;13:1062Fong et al.BBMT.2007;13:1201Baron et al.BBMT.2007;13:1041cGVHD：系统治疗指征：系统治疗指征Global severityHigh risk for mortality*Systemic treatment MildNo NoMildYes Yes ModerateNo/YesYesSevereNo/Yes Yes *Platelets 100,000/microliter or receiving steroids at time of diagnosis of CGVHD The benefits of graft-vs.-tumor effect and the risk of CGVHD need to be weighted Filipovic,BBMT 2005;12:945-955Steroids:Sullivan et al,Blood 1988;72.N=164Pred 1mg/kg vs Pred+AzathioprineNRM 21%vs 41%(p=0.03)Most common cause of death=relapseSteroids+CSA:Koc et al,Blood 2002;100.N=287RCT:Pred vs Ped+CSANo difference in TRM,OS,relapse,need for secondary cGVHD TxRelapse free survival better in prednisone only arm cGVHD:一线治疗一线治疗Martin.IntJHem.2004;79:221Stewart et al,Blood 2004;104Vogelsang.BJH.2004;125:435Lee,Blood.2005;105nProgression on steroidsnWithin 2-3 months if no improvement on steroidsnInability to taper steroids without recurrencenInability to tolerate steroids or calcineurin inhibitors(TTP)cGVHD:二线治疗二线治疗nSteroid pulsenCSAnTacronMMFnSirolimusnECPnPentostatinnRituximabnHydroxychloroquinenThalidomide/RevlimidnClofazaminenAzathioprinenATGnTLInLow dose MTXnDacluzimabnInfliximabnEtanerceptnImatinibnMontelukastcGVHD:二线治疗可选择药物二线治疗可选择药物cGVHD：二线治疗的疗效：二线治疗的疗效Lee et al,BBMT 2002Response rates in second line therapyNishimori H,Acta Med Okayama.2013;67(1):1-8.内内 容容nUpdate of knowledges in cGVHDnProgress in pathobiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHDKeratinocyte growth factor(KGF)nKGF treatment improves the restoration of thymic DCs and prevents the de novo generation of pathogenic CD4+T cells causing cGVHDnthe efficacy of palifermin treatment for cGVHD has being clinical studies to assess the role of the thymus as a target of cGVHD treatmentZhang Y,J Immunol(2007)179:3305-3314.靶向靶向TGF-/PDGF 信号途径治疗信号途径治疗Olivieri A.Blood.2013;122(25):4111-4118 Imatinib was planned for at least 6 months,starting at 100 mg/day during the first 15 days.In the absence of severe(grade 3-4 WHO)toxicity,the dosage was gradually increased to 400 mg/day.Treg therapy:Immunologic effects of 8 weeks of low-dose interleukin-2Koreth et al.N Engl J Med(2011)365:2055-2066.Immunologic effects of extended treatment with interleukin-2 on TregsKoreth et al N Engl J Med(2011)365:2055-2066.Retinoids for the Treatment of Chronic GVHDcGVHDHematology/OncologyDermatologyDentistry/Oral SurgeryRheumatologyInfectious DiseasesOphthalmologyPain/Palliative CareNutritional SupportRehabilitation MedicineNIH:multidisciplinaryapproachtocGVHDNIH National Consensus Guidelines for cGVHD Clinical Trials and Management