慢性移植物抗宿主病.ppt

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1、Chronic GVHD: Pathophysiology and Novel Therapeutic StrategiesTing LiuDepartment of Hematology West China HospitalSichuan University 2014. 4. Xiamen 内 容 nUpdate of knowledges in cGVHDnProgress in pathophysiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHD CIBMTR: GVHD 发 病 率Mat

2、ched Sibling Matched UnrelatedN=3158 N=941Acute GVHD Grade: II 18% 31% III-IV 16% 21%Chronic GVHD 42% 49% Ringdn O, et al. Blood. 2009;113:3110-3118. NIH 新 的 GVHD分 类 标 准 (2005)nAcute GVHD classic acute GVHD late-onset acute GVHDnChronic GHVD Classic chronic GVHD Overlap syndrome n NIH分 类 标 准 最 重 要 的

3、 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;2012:2

4、51-264 cGVHD发 病 的 危 险 因 素n Acute GVHDn Older age of recipient and donorn Female multiparous donorn Mismatched and unrelated donors n PBSC product n Disease type: CML, Aplastic anemia n High CD34 dose and/or T-cell dosen Second transplantsn DLIsn CMV? 影 响 cGVHD发 病 率 的 因 素n Classificationn Progressive

5、 poorest prognosisn Quiescentn de novon #1 risk factor: history of acute GVHDn Changing risk factorsn Older recipient agen Donors(unrelated, haploidentic) n Non-myeloablative conditioningn Peripheral blood stem cell sourcen Donor leukocyte infusions (DLI)Lee et al., Biol Blood Marrow Transplant 2003

6、; 9:215-33. 慢 性 GVHD的 临 床 表 现受 累 器 官 系 统 肯 定 为 慢 性 G VH D的 临 床 表 现 可 能 为 慢 性 G VH D的 临 床 表 现皮 肤 硬 皮 病 ， 扁 平 苔 藓 ， 白 癜 风 ， 疤 痕 性脱 发 ， 毛 发 角 化 过 度 ， 皮 肤 挛 缩 ， 甲床 发 育 异 常 湿 疹 样 皮 疹 , 皮 肤 干 燥 , 斑 丘 疹 , 脱发 , 色 素 沉 着黏 膜 扁 平 苔 藓 ， 口 干 症 ， 非 感 染 性 溃 疡 ，角 膜 糜 烂 /非 感 染 性 结 膜 炎 口 腔 干 燥 , 干 燥 性 角 结 膜 炎消 化 道 食 管

7、 狭 窄 ， 脂 肪 泻 食 欲 减 退 ， 吸 收 不 良 ， 体 重 减 轻 ，腹 泻 ， 腹 痛肝 脏 无 特 异 性 碱 性 磷 酸 酶 升 高 , 转 氨 酶 增 高 ， 胆管 炎 ， 高 胆 红 素 血 症泌 尿 生 殖 道 阴 道 狭 窄 ， 扁 平 苔 藓 非 感 染 性 阴 道 炎 ， 阴 道 萎 缩 肌 肉 骨 骼 /浆 膜 非 特 异 性 关 节 炎 ， 肌 炎 ， 肌 无 力 ， 浆膜 炎 ， 挛 缩 性 关 节 固 定 关 节 痛血 液 系 统 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

8、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n Epidermal cGVHDn Lichen planus-liken Papulosquamousn Ichthyosiform n Poikiloderman Keratosis pilaris-liken Acral erytheman Dermal cGVHDn Lichen-sclerosus-liken Dermal sclerosis n Subcutaneous cGVHDn Subcutaneous sclerosisn Fasc

9、iitis cGVHDn 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 impair

10、ment 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 用 危 险 度 积 分 代 替 了

11、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 nUpdate of knowledges in cGVHDnProgress in pathophysiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHD cGVHD的 病 理 生 理 学n Thymic damage and defective negative selection

12、n Deficiency of T-regsn TGF- and PDGF pathways mediated fibrosisn Th1/Th2/Th17 paradigm cytokinen 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n T-regs play a critical role in peripheral tolerance and

13、 development of cGVHDn CD4+ lymphopenia is a key factor in Treg homeostasis, and impaired reconstitution of Tregs can result in loss of tolerance and development of cGVHDn Adoptive transfer of Tregs and regulation to increase Tregs are considered to be eective clinical strategies TGF- 和 PDGF 信 号 通 路

14、 与 纤 维 化n cGVHD is characterized by brostic changes, TGF-1 levels are increased signicantly in the patientsn TGF- plays an important role in the generation and maintenance of Tregsn PDGF pathway may result in autoimmune e ects, and stimulatory antibodies to the PDGFR were found in all extensive cGVH

15、D patients n Imatinib 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n Donor CD4+ T cells can reciprocally di erentiate into Th1, Th2, and Th17 cellsn That mediate organ specic GVHD (Th1

16、: gut and liver; Th2: lung and skin; Th17: gut and skin)n Th1 and Th17 contribute to the development of cGVHD cGVHD： B细 胞 和 体 液 免 疫 异 常n A strong correlation between cGVHD and the presence of antibodies to Y chromosome encoded histocompatibility antigensn Elevated B cell-activating factor (BAFF) lev

17、els, which promotes survival and dierentiation of activated B cells, have been observed in patients with cGVHD. Genetic variation in BAFF was also correlated with cGVHDn cGVHD was associated with an increased number of B cells expressing high levels of Toll-like receptor 9 n In vivo depletion of B c

18、ells using rituximab can suppress the progression of complex cGVHD cGVHD SummaryThymusHSC CD8 CD4Treg BInflammatory cytokinesFibrosing cytokines AutoantibodyFibrosis and organ dysfunctionDeath from infection/organ failure AlloAuto 内 容nUpdate of knowledges in cGVHDnProgress in pathophysiology of cGVH

19、DnTreatment for cGVHDnNovel therapeutic strategies of cGVHD cGVHD的 药 物 预 防n Seatle group observed extended calcineurin inhibitor (CSA) treatment may decrease chronic GVHDn CSA 6 months vs 24 months in patients with prior aGVHD or evidence of subclinical chronic GVHD on skin biopsy = NO EFFECTn Thali

20、domide D+80 HIGHER rate of cGVHD and mortalityn Steroids until 6 months after transplantation HIGHER than expected incidence of severe cGVHDn Hydroxychloroquine+ CSA x 1 yr = NO EFFECT n MMF (D150) + CSA (D80)= NO EFFECTn Pre-transplant ATG may decrease cGVHDMangarelli et al. Hematologica. 2003;88:3

21、15, Kansu et al. Blood. 2001;98:3868. Chao et al. BBMT. 1996;2:96Ringden 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Global severity High risk for mortality * Systemic treatment Mild No NoMild Yes Yes Moderate No/Yes YesSevere No/Yes Y

22、es * Platelets 1 0 0 ,0 0 0 /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 2 0 0 5 ; 1 2 : 9 4 5 -9 5 5 Steroids: Sullivan et al, Blood 1988; 72. N=164 Pred 1mg/kg vs Pred+Azathioprine N

23、RM 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 线 治 疗 Martin. IntJHem. 2004;79:221 Stewart et

24、 al, Blood 2004; 104Vogelsang. BJH.2004;125:435 Lee, Blood.2005;105 n Progression on steroidsn Within 2-3 months if no improvement on steroidsn Inability to taper steroids without recurrencen Inability to tolerate steroids or calcineurin inhibitors (TTP)cGVHD: 二 线 治 疗 n Steroid pulsen CSAn Tacron MM

25、Fn Sirolimusn ECPn Pentostatinn Rituximabn Hydroxychloroquinen Thalidomide/Revlimid n Clofazaminen Azathioprinen ATGn TLIn Low dose MTXn Dacluzimabn Infliximabn Etanerceptn Imatinibn MontelukastcGVHD: 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 N

26、ishimori H, Acta Med Okayama. 2013;67(1):1-8. 内 容nUpdate of knowledges in cGVHDnProgress in pathobiology of cGVHDnTreatment for cGVHDnNovel therapeutic strategies of cGVHD Keratinocyte growth factor (KGF)n KGF treatment improves the restoration of thymic DCs and prevents the de novo generation of pa

27、thogenic CD4+ T cells causing cGVHDn 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 Imatinib was pla

28、nned 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-2 Koreth et al. N Engl J Med (2011) 365: 2055-2066. I

29、mmunologic effects of extended treatment with interleukin-2 on Tregs Koreth et al N Engl J Med (2011) 365: 2055-2066. Retinoids for the Treatment of Chronic GVHD cGVHDHematology/OncologyDermatology Dentistry/Oral SurgeryRheumatologyInfectious DiseasesOphthalmologyPain/Palliative Care Nutritional Support Rehabilitation MedicineNIH: multidisciplinary approach to cGVHDNIH National Consensus Guidelines for cGVHD Clinical Trials and Management