1、Chronic GVHD: Pathophysiology and Novel Therapeutic Strategies,Ting Liu Department of Hematology West China Hospital Sichuan University 2014. 4. Xiamen,內(nèi) 容,Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD,CIBMTR: GVHD 發(fā)病率,Ri

2、ngdn O, et al. Blood. 2009;113:3110-3118.,NIH 新的GVHD分類標(biāo)準(zhǔn)(2005),Acute GVHD classic acute GVHD late-onset acute GVHD Chronic GHVD Classic chronic GVHD Overlap syndrome NIH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,Filipovich AH, et al. Biol. Blood Marrow Transplant. 11(12), 94

3、5956 (2005).,GVHD classification after the NIH consensus conference,Pavletic S Z , and Fowler D H Hematology 2012;2012:251-264,cGVHD發(fā)病的危險(xiǎn)因素,Acute GVHD Older age of recipient and donor Female multiparous donor Mismatched and unrelated donors PBSC product Disease type: CML, Aplastic anemia High CD34 d

4、ose and/or T-cell dose Second transplants DLIs CMV?,影響cGVHD發(fā)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 stem cell s

5、ource Donor leukocyte infusions (DLI),Lee et al., Biol Blood Marrow Transplant 2003; 9:215-33.,慢性GVHD的臨床表現(xiàn),cGVHD: 多形性的皮膚病變,Epidermal cGVHD Lichen planus-like Papulosquamous Ichthyosiform Poikiloderma Keratosis pilaris-like Acral erythema Dermal cGVHD Lichen-sclerosus-like Dermal sclerosis Subcutaneo

6、us cGVHD Subcutaneous sclerosis Fasciitis,cGVHD,cGVHD ：口腔黏膜潰瘍,Treister N et al. Blood 2012;120:3407-3418,Prez-Simn J A et al. Haematologica 2012;97:1187-1195,不同類型cGVHD的預(yù)后,Multivariate risk factor profiles acute GVHD and chronic GVHD,Flowers M, et al. Blood.2011;117(11):3214-3219),cGVHD危險(xiǎn)度積分*,Mild no

7、 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 organ or site Lung score of 2,*采

8、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,Pavletic S Z , and Fowler D H Hematology 2012;2012:251-264,內(nèi) 容,Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD,cGVHD的病理生理學(xué),Thymic damage and defective negative selection Deficiency of T

9、-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：胸腺損害學(xué)說,外周免疫耐受：T-regs細(xì)胞缺陷,T-regs play a critical role in peripheral tolerance and development of cGVHD CD4+ lymphopenia is a

10、 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 信號(hào)通路與纖維化,cGVHD is characterized by brostic changes,

11、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 Imatinib may inhibit PDGFR, has been investig

12、ated for the refractory cGVHD,The Th1/Th2/Th17 的發(fā)育和平衡,Weaver CT. Immunity. 2006;24(6):677-88.,The Th1/Th2/Th17 發(fā)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: lung and skin; Th17: gut and skin) Th1 and Th17

13、contribute to the development of cGVHD,cGVHD：B細(xì)胞和體液免疫異常,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 dierentiation of activated B cells, have been obs

14、erved 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 progression of complex cGVHD,cGVHD Summary,Infl

15、ammatory cytokines,Fibrosing cytokines,Autoantibody,Fibrosis and organ dysfunction,Death from infection/organ failure,Allo,Auto,內(nèi) 容,Update of knowledges in cGVHD Progress in pathophysiology of cGVHD Treatment for cGVHD Novel therapeutic strategies of cGVHD,cGVHD的藥物預(yù)防,Seatle group observed extended c

16、alcineurin 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 until 6 months after transplantation HIGHER than expec

17、ted 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;2:96 Ringden et al. Exp Hem.1985;13:1062 Fong et al.

18、BBMT. 2007;13:1201 Baron et al. BBMT. 2007;13:1041,cGVHD：系統(tǒng)治療指征,* 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;

19、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 Relapse free survival better in prednisone only arm,cGVHD: 一線治

20、療,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 to tolerate steroids or calcineurin inhibitors (TTP),cGVHD: 二

21、線治療,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: 二線治療可選擇藥物,cGVHD：二線治療的療效,Lee et al, BBMT 2002,Response rates in second line therapy,Ni

22、shimori H, Acta Med Okayama. 2013;67(1):1-8.,內(nèi) 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 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 信號(hào)途徑治療,Olivieri A. Blood. 2013;122(25):4111-4118,Ima