慢性移植物抗宿主病VIP

1、Chronic GVHD: Pathophysiology and Novel Therapeutic Strategies,Ting Liu Department of Hematology West China Hospital Sichuan University 2014. 4. Xiamen,.,内 容,Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD,.,CIBMTR: GVHD 发病

2、率,Ringdn O, et al. Blood. 2009;113:3110-3118.,.,NIH 新的GVHD分类标准(2005),Acute GVHD classic acute GVHD late-onset acute GVHD Chronic GHVD Classic chronic GVHD Overlap 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(1

3、2), 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 GVHD Older age of recipient and donor Female multiparous donor Mismatched and unrelated donors PBSC product Disease type: CML, Aplastic anemia H

4、igh CD34 dose and/or T-cell dose Second transplants DLIs CMV?,.,影响cGVHD发病率的因素,Classification Progressive poorest prognosis Quiescent de novo #1 risk factor: history of acute GVHD Changing risk factors Older recipient age Donors(unrelated, haploidentic) Non-myeloablative conditioning Peripheral blood

5、 stem cell source Donor 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 cGVHD Lichen planus-like Papulosquamous Ichthyosiform Poikiloderma Keratosis pilaris-like Acral erythema Dermal cGVHD Lichen-sclerosus-like Dermal scle

6、rosis Subcutaneous cGVHD Subcutaneous sclerosis Fasciitis,.,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

7、-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 disability Three or more organs with max score 1 One organ with max score 2 Lung score of 1 Severe major disability Score of 3 in any orga

8、n or site Lung 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 cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD,.,cGVHD的病理生理学,Thymic damage and defective

9、negative selection Deficiency of T-regs TGF- and PDGF pathways mediated fibrosis Th1/Th2/Th17 paradigm cytokine Dysregulated 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 de

10、velopment of cGVHD CD4+ lymphopenia is a key factor in Treg homeostasis, and impaired reconstitution of Tregs can result in loss of tolerance and development of cGVHD Adoptive 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,c

11、GVHD is characterized by brostic changes, TGF-1 levels are increased signicantly in the patients TGF- plays an important role in the generation and maintenance of Tregs PDGF pathway may result in autoimmune eects, and stimulatory antibodies to the PDGFR were found in all extensive cGVHD patients Ima

12、tinib 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 cells That mediate organ specic GVHD (Th1: gut and liver; Th2: lu

13、ng 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 antigens Elevated B cell-activating factor (BAFF) levels, which promotes survival and d

14、ierentiation of activated B cells, have been observed in patients with cGVHD. Genetic variation in BAFF was also correlated with cGVHD cGVHD 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

15、 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 cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies

16、of cGVHD,.,cGVHD的药物预防,Seatle group observed extended calcineurin inhibitor (CSA) treatment may decrease chronic GVHD CSA 6 months vs 24 months in patients with prior aGVHD or evidence of subclinical chronic GVHD on skin biopsy = NO EFFECT Thalidomide D+80 HIGHER rate of cGVHD and mortality Steroids

17、until 6 months after transplantation HIGHER than expected incidence of severe cGVHD Hydroxychloroquine+ CSA x 1 yr = NO EFFECT MMF (D150) + CSA (D80)= NO EFFECT Pre-transplant ATG may decrease cGVHD,Mangarelli et al. Hematologica. 2003;88:315, Kansu et al. Blood. 2001;98:3868. Chao et al. BBMT. 1996

18、;2:96 Ringden et al. Exp Hem.1985;13:1062 Fong et al. BBMT. 2007;13:1201 Baron 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

19、2005; 12: 945-955,.,Steroids: Sullivan et al, Blood 1988; 72. N=164 Pred 1mg/kg vs Pred+Azathioprine NRM 21% vs 41% (p=0.03) Most common cause of death = relapse Steroids + CSA: Koc et al, Blood 2002; 100. N=287 RCT: Pred vs Ped+CSA No difference in TRM, OS, relapse, need for secondary cGVHD Tx Rela

20、pse free survival better in prednisone only arm,cGVHD: 一线治疗,Martin. IntJHem. 2004;79:221 Stewart et al, Blood 2004; 104 Vogelsang. BJH.2004;125:435 Lee, Blood.2005;105,.,Progression on steroids Within 2-3 months if no improvement on steroids Inability to taper steroids without recurrence Inability t

21、o tolerate steroids or calcineurin inhibitors (TTP),cGVHD: 二线治疗,.,Steroid pulse CSA Tacro MMF Sirolimus ECP Pentostatin Rituximab Hydroxychloroquine Thalidomide/Revlimid,Clofazamine Azathioprine ATG TLI Low dose MTX Dacluzimab Infliximab Etanercept Imatinib Montelukast,cGVHD: 二线治疗可选择药物,.,cGVHD：二线治疗的

22、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 cGVHD Progress in pathobiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD,.,Keratinocyte growth factor (KGF),KGF treatment improves the

23、 restoration of thymic DCs and prevents the de novo generation of pathogenic CD4+ T cells causing cGVHD the 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,Imati