慢性移植物抗宿主病

Acute GVHD Grade:
II
III-IV Chronic GVHD
ห้องสมุดไป่ตู้
18%
16% 42%
31%
21% 49%
Ringdén 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
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 ↓ High CD34 dose and/or T-cell dose Second transplants DLIs CMV?
不同类型cGVHD的预后

Pérez-Simón J A et al. Haematologica 2012;97:1187-1195
Multivariate risk factor profiles acute GVHD and chronic GVHD
Flowers M, et al. Blood.2011;117(11):3214-3219)
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), 945–956 (2005).
GVHD classification after the NIH consensus conference
cGVHD Summary
CD8
HSC
Thymus
CD4 Treg
Inflammatory cytokines
Fibrosing cytokines
Fibrosis and organ dysfunction
B
Autoantibody
Death from infection/organ failure
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
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 differentiate into Th1, Th2, and Th17 cells That mediate organ specific GVHD (Th1: gut and liver; Th2: lung and skin; Th17: gut and skin) Th1 and Th17 contribute to the development of cGVHD
TGF-β 和 PDGF 信号通路与纤维化
cGVHD is characterized by
fibrostic changes, TGF-β1 levels are increased significantly in the patients TGF-β plays an important role in the generation and maintenance of Tregs PDGF pathway may result in autoimmune effects, and stimulatory antibodies to the PDGFR were found in all extensive cGVHD patients Imatinib may inhibit PDGFR, has been investigated for the refractory 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 differentiation 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 progression of complex cGVHD
内
容
Update of knowledges in cGVHD
Progress in pathophysiology of cGVHD
Treatment for cGVHD
Dermal cGVHD Lichen-sclerosus-like Dermal sclerosis
Subcutaneous cGVHD Subcutaneous sclerosis Fasciitis
cGVHD

cGVHD ：口腔黏膜溃疡
Treister N et al. Blood 2012;120:3407-3418
非特异性关节炎，肌炎，肌无力，浆 关节痛 膜炎，挛缩性关节固定 无特异性 血小板减少, 嗜酸性细胞增多，自 身免疫性血细胞减少
肺
闭塞性细支气管炎
闭塞性细支气管炎伴机化性肺炎， 间质性肺炎
cGVHD: 多形性的皮肤病变

Epidermal cGVHD Lichen planus-like Papulosquamous Ichthyosiform Poikiloderma Keratosis pilaris-like Acral erythema
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
The 5 Tenets of cGVHD Thymic damage and defective negative selection Deficiency of T-regs TGF-β and PDGF pathways mediated fibrosis Th1/Th2/Th17 paradigm cytokine Dysregulated B-cell and humoral immunity
Takanori Teshima, ASBMT 2008
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 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 effective clinical strategies
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 stem cell source Donor leukocyte infusions (DLI)
内
容
Update of knowledges in cGVHD
Progress in pathophysiology of cGVHD
Treatment for cGVHD
Novel therapeutic strategies of cGVHD
CIBMTR: GVHD 发病率
Matched Sibling N=3158 Matched Unrelated N=941
Lee et al., Biol Blood Marrow Transplant 2003; 9:215-33.
慢性GVHD的临床表现
受累器官系统 皮肤 可能为慢性GVHD的临床表现 硬皮病，扁平苔藓，白癜风，疤痕性 湿疹样皮疹, 皮肤干燥, 斑丘疹, 脱 脱发，毛发角化过度，皮肤挛缩，甲 发, 色素沉着 床发育异常 肯定为慢性GVHD的临床表现
Severe – major disability • Score of 3 in any organ 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
黏膜
消化道 肝脏 泌尿生殖道 肌肉骨骼/浆膜 血液系统
扁平苔藓，口干症，非感染性溃疡， 口腔干燥, 干燥性角结膜炎 角膜糜烂/非感染性结膜炎
食管狭窄，脂肪泻 无特异性 阴道狭窄，扁平苔藓 食欲减退，吸收不良，体重减轻， 腹泻，腹痛 碱性磷酸酶升高, 转氨酶增高，胆 管炎，高胆红素血症 非感染性阴道炎，阴道萎缩
Chronic GVHD: Pathophysiology and Novel Therapeutic Strategies
Ting Liu Department of Hematology West China Hospital Sichuan University 2014. 4. Xiamen