慢性移植物抗宿主病

Chronic GVHD: Pathophysiology and Novel Therapeutic Strategies,Ting LiuDepartment of Hematology West China HospitalSichuan University 2014. 4. Xiamen,内 容,Update of knowledges in cGVHDProgress in pathophysiology of cGVHDTreatment for cGVHDNovel therapeutic strategies of cGVHD,CIBMTR: GVHD 发病率,Ringdn O, et al. Blood. 2009;113:3110-3118.,NIH 新的GVHD分类标准(2005),Acute GVHDclassic acute GVHDlate-onset acute GVHDChronic GHVDClassic chronic GVHDOverlap syndrome NIH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;2012:251-264,cGVHD发病的危险因素,Acute GVHDOlder age of recipient and donorFemale multiparous donorMismatched and unrelated donors PBSC product Disease type: CML, Aplastic anemia High CD34 dose and/or T-cell doseSecond transplantsDLIsCMV?,影响cGVHD发病率的因素,ClassificationProgressive poorest prognosisQuiescentde novo#1 risk factor: history of acute GVHDChanging risk factorsOlder recipient ageDonors(unrelated, haploidentic)Non-myeloablative conditioningPeripheral blood stem cell sourceDonor leukocyte infusions (DLI),Lee et al., Biol Blood Marrow Transplant 2003; 9:215-33.,慢性GVHD的临床表现,cGVHD: 多形性的皮肤病变,Epidermal cGVHDLichen planus-likePapulosquamousIchthyosiform PoikilodermaKeratosis pilaris-likeAcral erythemaDermal cGVHDLichen-sclerosus-likeDermal sclerosisSubcutaneous cGVHDSubcutaneous sclerosisFasciitis,cGVHD,cGVHD ：口腔黏膜溃疡,Treister N et al. Blood 2012;120:3407-3418,Prez-Simn J A et al. Haematologica 2012;97:1187-1195,不同类型cGVHD的预后,Multivariate risk factor profiles acute GVHD and chronic GVHD,Flowers M, et al. Blood.2011;117(11):3214-3219),cGVHD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cGVHD危险度积分,Pavletic S Z , and Fowler D H Hematology 2012;2012:251-264,内 容,Update of knowledges in cGVHDProgress in pathophysiology of cGVHDTreatment for cGVHDNovel therapeutic strategies of cGVHD,cGVHD的病理生理学,Thymic damage and defective negative selectionDeficiency of T-regsTGF- and PDGF pathways mediated fibrosisTh1/Th2/Th17 paradigm cytokineDysregulated B-cell and humoral immunity,Takanori Teshima, ASBMT 2008,The 5 Tenets of cGVHD,中央免疫耐受：胸腺损害学说,外周免疫耐受：T-regs细胞缺陷,T-regs play a critical role in peripheral tolerance and development of cGVHDCD4+ lymphopenia is a key factor in Treg homeostasis, and impaired reconstitution of Tregs can result in loss of tolerance and development of cGVHDAdoptive transfer of Tregs and regulation to increase Tregs are considered to be eective clinical strategies,TGF- 和 PDGF 信号通路与纤维化,cGVHD is characterized by brostic changes, TGF-1 levels are increased signicantly in the patientsTGF- plays an important role in the generation and maintenance of TregsPDGF pathway may result in autoimmune eects, and stimulatory antibodies to the PDGFR were found in all extensive cGVHD patientsImatinib may inhibit PDGFR, has been investigated for the refractory cGVHD,The Th1/Th2/Th17 的发育和平衡,Weaver CT. Immunity. 2006;24(6):677-88.,The Th1/Th2/Th17 发育和平衡,Donor CD4+ T cells can reciprocally dierentiate into Th1, Th2, and Th17 cellsThat mediate organ specic GVHD (Th1: gut and liver; Th2: lung and skin; Th17: gut and skin)Th1 and Th17 contribute to the development of cGVHD,cGVHD：B细胞和体液免疫异常,A strong correlation between cGVHD and the presence of antibodies to Y chromosome encoded histocompatibility antigensElevated B cell-activating factor (BAFF) levels, which promotes survival and dierentiation of activated B cells, have been observed in patients with cGVHD. Genetic variation in BAFF was also correlated with cGVHDcGVHD was associated with an increased number of B cells expressing high levels of Toll-like receptor 9 In vivo depletion of B cells using rituximab can suppress the progression of complex cGVHD,cGVHD Summary,Inflammatory cytokines,Fibrosing cytokines,Autoantibody,Fibrosis and organ dysfunction,Death from infection/organ failure,Allo,Auto,内 容,Update of knowledges in cGVHDProgress in pathophysiology of cGVHDTreatment for cGVHDNovel therapeutic strategies of cGVHD,cGVHD的药物预防,Seatle group observed extended calcineurin inhibitor (CSA) treatment may decrease chronic GVHDCSA 6 months vs 24 months in patients with prior aGVHD or evidence of subclinical chronic GVHD on skin biopsy = NO EFFECTThalidomide D+80 HIGHER rate of cGVHD and mortalitySteroids until 6 months after transplantation HIGHER than expected incidence of severe cGVHDHydroxychloroquine+ CSA x 1 yr = NO EFFECTMMF (D150) + CSA (D80)= NO EFFECTPre-transplant ATG may decrease cGVHD,Mangarelli 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;13:1041,cGVHD：系统治疗指征,* 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: 945-955,Steroids: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,Martin. IntJHem. 2004;79:221Stewart et al, Blood 2004; 104Vogelsang. BJH.2004;125:435Lee, Blood.2005;105,Progression on steroidsWithin 2-3 months if no improvement on steroidsInability to taper steroids without recurrenceInability to tolerate steroids or calcineurin inhibitors (TTP),cGVHD: 二线治疗,Steroid pulseCSATacroMMFSirolimusECPPentostatinRituximabHydroxychloroquineThalidomide/Revlimid,ClofazamineAzathioprineATGTLILow dose MTXDacluzimabInfliximabEtanerceptImatinibMontelukast,cGVHD: 二线治疗可选择药物,cGVHD：二线治疗的疗效,Lee et al, BBMT 2002,Response rates in second line therapy,Nishimori H, Acta Med Okayama. 2013;67(1):1-8.,内 容,Update of knowledges in cGVHDProgress in pathobiology of cGVHDTreatment for cGVHDNovel therapeutic strategies of cGVHD,Keratinocyte growth factor (KGF),KGF treatment improves the restoration of thymic DCs and prevents the de novo generation of pathogenic CD4+ T cells causing cGVHDthe ecacy of palifermin treatment for cGVHD has being clinical studies to assess the role of the thymus as a target of cGVHD treatment,Zhang Y, J Immunol (2007) 179: 3305-3314.,靶向TGF- / PDGF 信号途径治疗,Olivieri A. Blood. 2013;122(25):4111-4118,Imatinib was p