急性移植物抗宿主病的防治

1、会计学1急性移植物抗宿主病的防治急性移植物抗宿主病的防治第1页/共52页020406080100% Grades 2-4 GVHDHLA-identical related1-Ag-mismatchedrelated2/3-Ag-mismatchedrelatedHLA-matchedunrelated1-Ag-mismatchedunrelatedAdapted from Szydlo R, J Clin Oncol 1997第2页/共52页Infection (16%)Other (29%)OrganFailure (6%)Primary Disease(33%)New Malignanc

2、y (1%)GVHD (15%)SUM-WW11_17.pptInfection (12%)Other (21%)Primary Disease (47%)GVHD (14%)Organ Failure (4%)New Malignancy (1%)第3页/共52页（Billingham，1966）第4页/共52页第5页/共52页第6页/共52页第7页/共52页第8页/共52页第9页/共52页第10页/共52页Shono et al. Blood, 2010 115: 5401-5411Suppression of HematopoiesisCytopenia Delayed Immune r

3、ecovery AnemiaSever infectionBleeding ComplicationsGVHD Targets: Bone marrow?第11页/共52页 重度重度aGVHD患者多出现一系、两系甚至全血细胞减少，对造血刺激因子治患者多出现一系、两系甚至全血细胞减少，对造血刺激因子治疗反应欠佳，治疗上依赖成分输血。疗反应欠佳，治疗上依赖成分输血。 aGVHD是造血功能低下的主要危险因素，血小板减少是影响预后的因素之是造血功能低下的主要危险因素，血小板减少是影响预后的因素之一。一。aGVHD合并造血抑制者预后差合并造血抑制者预后差No GVHDGVHDBicytopeniaPan

4、cytopeniaCytopenia(one lineage)11.25%32.43%39.28%68.93%35.62%Non Relapse Mortality % GVHDCytopenia(one lineage)Bicytopenia PancytopeniaIncidence %36.5%27%11.2%LeukocytesPlateletsNon Relapse Mortality %15.3%42.6%第12页/共52页第13页/共52页15ncGVHD in murine models is more donor T cell dose and survival time d

5、ependent nHD donor CD4+ cells are more potent in induction of aGVHD, LD donor CD8+ T cells are more potent in induction of cGVHD nDonor CD8+ cells in transplants are sufficient to induce aGVHD, the subsequent development of cGVHD requires help from de novo-generated donor-derived T cells developing

6、in the GVHD damaged thymus nde novo-generated donor-derived CD4+ T cells but not CD8+ T cells can mediate thymic damage and cGVHD development nDamage to mTECs by donor CD8+ T cells leads to defective negative selection of de novo-generated autoreactive T cells early after HCTWu Tao, et al. JI 2013第1

7、4页/共52页供者方面因素受者方面因素第15页/共52页第16页/共52页第17页/共52页第18页/共52页EBMTELN recommendations， 2013第19页/共52页EBMTELN recommendations， 2013第20页/共52页22APCT naiveAgIL-1, TNFApoptosis Ag processing/presentationThalidomide, Chloroquine, Tresperimus T-cell receptorATG, OKT3， Visilizumab Co-stimulationATG, CTLA4-Ig, anti-

8、CD40/CD40L Early activationCyclosporine, Tacrolimus Late activationSirolimus, Leflunomide IL-2 receptorDaclizumab, Basiliximab Cell cycleMethotrexate, Mycophenolate Cytokines Methotrexate, Mycophenolate, anti-TNF Apoptosis ATG, Campath-1（anti-CD52）IL-2rIL-2 第21页/共52页第22页/共52页Andrew C.Harris. British

9、 J of Haematology. 160, 288302 (2013) 第23页/共52页第24页/共52页第25页/共52页 累及的靶器官主要为皮肤、肠道和肝脏皮肤GVHD(斑丘疹)：最常见和最早发生, HLA相合同胞移植发生中位天数20天肠道GVHD（腹泻）：往往出现在皮肤 GVHD之后，常在1个月之内发生 肝脏GVHD（黄疸）：出现相对较晚， 常在移植后30-40天之后出现主要靶器官表现第26页/共52页分期皮 肤肝脏肠道斑丘疹体表面积斑丘疹体表面积25%25%胆红素：胆红素：343450mol/L50mol/L腹泻量腹泻量500 ml/500 ml/日日斑丘疹体表面积斑丘疹体表面积

10、50%50%胆红素：胆红素：5151102mol/L102mol/L腹泻量腹泻量1000 ml/1000 ml/日日全身广泛红斑丘疹全身广泛红斑丘疹体表面积体表面积50%50%胆红素：胆红素：103103255mol/L255mol/L腹泻量腹泻量1500 ml/1500 ml/日日全身广泛红斑丘疹全身广泛红斑丘疹伴伴水疱或皮肤剥脱水疱或皮肤剥脱 胆红素：胆红素：255 mol/Lmol/L 大量腹泻大量腹泻伴腹痛，肠梗阻伴腹痛，肠梗阻第27页/共52页分度 皮肤 肠道 肝脏生活能力(轻度)-0 00 0正常(中度)-轻度降低(重度)- -明显降低(极重度) - -极度降低第28页/共52页第

11、29页/共52页第30页/共52页第31页/共52页一线治疗第32页/共52页MP 2mg/kg/d与与 MP 10mg/kg/d治疗治疗aGVHD，两，两者实际生存率无明显差异者实际生存率无明显差异第33页/共52页H. Joachim Deeg. BLOOD, 2007,109:4119-4226治疗有反应：治疗有反应：5天后剂量减半至1mg/kg；1mg/kg之后减药：10-30天减半治疗无反应：治疗无反应：二线治疗第34页/共52页ASBMT recommendations，2012第35页/共52页ASBMT recommendations，2012第36页/共52页ASBMT re

12、commendations，2012第37页/共52页第38页/共52页第39页/共52页第40页/共52页第41页/共52页第42页/共52页第43页/共52页第44页/共52页第45页/共52页47ncGVHD in murine models is more donor T cell dose and survival time dependent nHD donor CD4+ cells are more potent in induction of aGVHD, LD donor CD8+ T cells are more potent in induction of cGVHD n

13、Donor CD8+ cells in transplants are sufficient to induce aGVHD, the subsequent development of cGVHD requires help from de novo-generated donor-derived T cells developing in the GVHD damaged thymus nde novo-generated donor-derived CD4+ T cells but not CD8+ T cells can mediate thymic damage and cGVHD development nDamage to mTECs by donor CD8+ T cells leads to defective negative selection of de novo-generated autoreactive T cells early after HCTWu Tao, et al. JI 20