异基因造血干细胞移植后的移植物抗白血病作用的临床观察

移植物抗白血病作用（GVL）是异基因造血干细胞移植后,引起造血系统肿瘤持续缓解状态的一种免疫介导的反应。目前,对GVL的机理仍不清楚。临床上观察到,在GVL出现前,病人多经历了一个急或慢性的移植物抗宿主病（GVHD）过程。GVHD使受者正常的组织和细胞受到损伤,而同时产生     

异基因造血干细胞移植治疗恶性血液病临床疗效分析

目的总结162例异基因造血干细胞移植（allo-HSCT）[包括：同胞allo-HSCT125例．非血缘关系allo-HSCT30例和非清髓异基因外周血造血干细胞移植（allo-PBSCT）7例1治疗恶性血液病疗效和生存状况。方法慢性粒细胞白血病（CML）患者62例，急性髓系白血病（AML）患者58例，急性淋巴细胞白血病（ALL）患者28例．骨髓增生异常综合征（MDS）6例，多发性骨髓瘤（MM）3例，非霍奇金淋巴瘤（NHL）3例，慢性粒单细胞性白血病（CMML）1例．霍奇金淋巴瘤（HD）1例。经预处理，进行人类白细胞抗原（HLA）相合的同胞异基因骨髓移植（allo-BMT）27例．allo-PBSCT98例和非血缘关系allo-BMT4例，非血缘关系aUo-PBSCT26例．HLA相合的同胞非清髓allo-PBSCT7例。非血缘关系allo-HSCT患者采用长程加强的移植物抗宿主病（GVHD）的预防方案（将环孢菌素A提前至预处理开始时使用，同时加用霉酚酸酯）。结果移植后中位随访38（2-259）个月。allo-HSCT患者长期DFS为54、9％（89／162），CML至今DFS为61-3％（38／62），AML至今DFS为56，9％（33／58），ALL至今DFS为39-3％（11／28）．MDS至今DFS为83-3％（5／6），3例NHL存活1例，1例CMML存活．3例MM均死亡．霍奇金淋巴瘤（HD）1例死亡。移植后100d内移植相关死亡率（TRM）19．8％（32／162），死亡原因分别为急性GVHD、播散性感染、复发和植入失败；移植后100d至2年内TRM为24、7％（40／162）．死亡原因分别为慢性GVHD、CMV感染和疾病复发，1例于移植后1413d死亡．其余移植超过2年均存活，死亡原因是慢性GVHD合并感染，最长生存已11年。结论allo-HSCT可使相当部分白血病患者获得长期无病存活．治疗MDS效果良好．治疗MM效果很差。该组患者移植后100d内死亡原因主要是急性GVHD：移植后100d至2年内死亡的主要原因是慢性GVHD和CMV感染、疾病复发；故除正确处理移植相关并发症?     

双色间期荧光原位杂交检测异基因造血干细胞移植后性染色体嵌合状态的临床意义

目的　探讨异基因造血干细胞移植(allogeneic hematopietic stem cell transplantation,allo-HSCT)后嵌合状态与微小残留病(minimal residual disease,MRD)和移植后白血病复发的关系。方法　5 7例白血病患者接受性别不同的供体HSCT,在移植后不同时期留取骨髓细胞,采用双色间期荧光原位杂交(interphase fluorescence in situ hybridization,I- FISH)技术对性染色体和bcr/ abl融合基因进行监测,SPSS10 .0统计软件分析嵌合状态与MRD和白血病复发的关系。结果　I- FISH测定性染色体和bcr/ abl融合基因敏感性高于常规核型分析;嵌合状态与MRD呈负相关(r=- 0 .96 90 ,P<0 .0 1) ;在移植早期(3个月)混合嵌合状态比完全嵌合状态患者复发率高,嵌合状态和MRD与白血病复发具有相关性(r=- 82 4 0 ,P<0 .0 1;r=- 90 4 0 ,P<0 .0 1) ;嵌合率下降出现在白血病血液学复发前。结论　I- FISH用于allo- HSCT后的MRD监测具有高特异性和敏感性,性染色体作为性别不同的allo- HSCT后MRD的监测其临床价值与肿瘤特异性基因标志相同,嵌合状态与MRD呈负相关,嵌合状态和MRD与移植后白血病复发相关,嵌合率的下降可作为移植后白血病复发的分子遗传学标志。     

干扰素-γ在异基因造血干细胞移植中的作用

干扰素-γ(IFN-γ)是最重要的Th1型细胞因子之一,可由多种类型的免疫活性细胞产生.IFN-γ具有多种生物学效应,并可能在接受了异基因造血干细胞移植(allo-HSCT)的患者发生移植物抗宿主病(GVHD)的过程中起了关键性的作用.IFN-γ最初被认为是急性GVHD过程中介导组织损伤的关键因素之一,且与GVHD严重...     

清肿瘤性异基因造血干细胞移植

标准的清髓性异基因造血干细胞移植(allo-HSCT)对于需代替治疗的造血与免疫系统的非恶性疾病,应当是合理或足够的;然而,对于恶性血液病患者,清除患者骨髓造血组织,成功重建异体正常造血与免疫系统,并不一定能完全治愈恶性血液病,因为白血病(干)细胞并非只限骨髓中存在,它可浸润骨髓之外的其他任何组织。临床实践证实,allo-HSCT后仍然有30%左右的患者疾病复发,特别是具有高危因素或难治复发患者复发率可高达40%～70%以上。这些复发的白血病细胞几乎全系源自患者移植前本身的白血病细胞,其中半数患者以髓外部位复发开始,有证据提示,清髓性移植并没有完全杀灭患者体内的白血病细胞,特别是那些对化放疗不敏感或栖居在髓外"庇护所"中的白血病干细胞,最终导致疾病复发。因此笔者提出并建立了一个清肿瘤性异体造血干细胞移植(TAHSCT)的概念,在临床上对其进行了初步的探讨。其内容贯穿于移植技术全过程的各个环节,但主要为应用个体化清肿瘤性预处理方案和加强移植后免疫治疗。     

过继免疫疗法在异基因造血干细胞移植中的应用

近年来免疫识别等方面取得的一些研究进展为克服或逆转异基因造血干细胞移植（Allo－HSCT）的主要伴发症——继发性免疫缺陷和移植物抗宿病（GVHD）提供了新思路：如过继输注病毒特异性T淋巴细胞,重建移植病人的特异性免疫功能;Allo-HSCT后行供体淋巴细胞输入（DLI）延长病人的缓解期,以及诱导移植物抗白血病（GVL）效应等。因此,本文就近几年来异基因造血干细胞移植中过继免疫疗法的某些研究进展进行综述。     

异基因造血干细胞移植后骨髓免疫微环境重建研究

GVHD 和GVL 是影响异基因造血干细胞移植术成败的关键因素。骨髓不仅是造血器官,更是免疫器官,骨髓中的免疫微环境关乎移植后造血重建、免疫功能重建、移植后白血病复发。本文将从骨髓微环境的病理生理特点、异基因造血干细胞移植后免疫功能重建、骨髓免疫微环境与移植后造血恢复及移植后白血病复发等角度,综述近年来关于异基因造血干细胞移植后骨髓免疫微环境重建与造血重建和白血病复发相关研究情况。     

异基因造血干细胞移植后免疫功能重建

异基因造血干细胞移植(allo-HSCT)，岳患者的免疫功能受到严重损伤，移植后免疫功能低下主要表现在：①免疫个体发生学过程再现的削弱；②缺乏长期稳定的供体免疫功能的转移； ③移植物抗宿主病(GVHD)对免疫功能的影响； ④胸腺功能的降低。临床实践证实，清髓性治疗后患者的免疫功能处于麻痹状态可以持续1年之久。     

白血病患者异基因造血干细胞移植后T细胞免疫重建的研究

目的 通过分析TCR Vβ基因片段选择性扩增，了解白血病患者异基因外周血干细胞移植后T淋巴细胞的免疫重建及其在移植物抗宿主病(GVHD)患者中的表达特点．方法 采用RT—PCR扩增10例移植后患者外周血的单个核细胞的TCR Vβ24个基因片段，分析其TCR Vβ基因的表达情况，GVHD患者的PCR产物进一步经基因扫描分析确定T细胞克隆性．结果 经24个Vβ引物所分别进行的RT—PCR检测TCR Vβ各亚家族基因的表达情况，发现10例病人外周血与正常人表达24个Vβ亚家族有明显的不同，病人的部分Vβ亚家族T细胞仍未能重建，仅表达5-22个亚家族基因；9例GVHD患者外周血仅表达2—8个TCR Vβ亚细胞生长．结论 移植后病人外周血淋巴细胞TCR Vβ基因片段部分受抑制，部分基因片段呈选择性扩增．GVHD患者有Vβ3和Vβ8基因的优势表达，并有克隆性T细胞生成．     

FISH检测性染色体在鉴别急性淋巴细胞白血病异基因造血干细胞移植后髓外复发与淋巴细胞增殖性疾病中的临床应用

目的 探讨荧光原位杂交(fluorescence in situ hybridization,FISH)在鉴别急性淋巴细胞白血病(acute lymphocytic leukemia,ALL)异基因造血干细胞移植(allogeneic hernatopoietic stem celltransplantation,allo-HSCT)后髓外复发与移植后淋巴细胞增殖性疾病(post-transplant lymphoproliferativedisease,PTLD)的可行性.方法 对6例ALL接受性别不同供者HSCT后出现淋巴结肿大或局部包块的患者,用FISH检测患者骨髓或肿瘤组织中性染色体嵌合状态和原位杂交检测肿瘤细胞内EB病毒RNA(Epstein-Barr virus,EBV-RNA).结果 6例患者骨髓细胞性染色体均示100%供者型.肿瘤组织中性染色体嵌合状态:3例受者型分别为100%、100%、98.0%,诊断白血病髓外复发;3例供者型分别为98.5%、96.0%,91.5%,诊断为PTLD.2例供者型患者EBV-RNA和EBV潜伏膜蛋白-1(latent membraneprotein,LMP-1)均阳性,其他患者阴性.经治疗3例髓外复发与3例PTLD患者分别有1例部分缓解,1例完全缓解,另4例患者治疗无效死亡.结论 接受性别不同供者HSCT后出现髓外复发或PTLD的ALlL患者,通过FISH检测患者肿瘤组织中性染色体嵌合状态是鉴别髓外复发与PTLD的十分有效手段.     

KIR-ligand mismatch in allogeneic hematopoietic stem cell transplantation

KIR-ligand mismatch in the graft-versus-host (GVH) direction between donor and recipient in allogeneic stem cell transplantation (ASCT) may trigger NK cell alloreactivity. Such KIR-ligand mismatch has been associated with improved survival after haploidentical ASCT for acute myeloid leukemia (AML). Its role in unrelated ASCT has been more controversial. In an analysis of 190 unrelated ASCTs for hematological malignancies, we observed that KIR-ligand mismatch was associated with increased transplantation related mortality (TRM) and decreased overall survival. The increased TRM was a consequence of a higher rate of infections. Thus, the presence of alloreactive NK cells can potentially interfere with effective immunity to infections in the early post-transplantation period. Here, we review the discrepancies in published reports on KIR-ligand mismatch in unrelated ASCT.     

Clinical tolerance in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) has been a curative therapeutic option for a wide range of immune hematologic malignant and non-malignant disorders including genetic diseases and inborn errors. Once in the host, allogeneic transplanted cells have not only to ensure myeloid repopulation and immunological reconstitution but also to acquire tolerance to host human leukocyte antigens via central or peripheral mechanisms. Peripheral tolerance after allogeneic HSCT depends on several regulatory mechanisms aimed at blocking alloimmune reactivity while preserving immune responses to pathogens and tumor antigens. Patients transplanted with HSCT represent an ideal model system in humans to identify and characterize the key cellular and molecular players underlying these mechanisms. The knowledge gained from these studies has allowed the development of novel therapeutic strategies aimed at inducing long-term peripheral tolerance, which can be applicable not only in allogeneic HSCT but also in autoimmune diseases and solid-organ transplantation. In the present review, we describe Type 1 regulatory T cells, initially discovered and characterized in chimeric patients transplanted with human leukocyte antigen-mismatched HSCT, and how their presence correlates to tolerance induction and maintenance. Furthermore, we summarize different cell therapy approaches with regulatory T cells, designed to facilitate tolerance induction, minimizing pharmaceutical interventions.     

白消安在非亲缘异基因造血干细胞移植预处理中的应用

背景：口服白消安剂型胃肠道吸收不稳定,影响异基因造血干细胞疗效且毒性增加。静脉剂型白消安在国内最近几年用于临床,但在非亲缘异基因移植预处理中应用的相关报道甚少。 目的：探讨静脉剂型白消安在非亲缘异基因造血干细胞移植预处理中应用的疗效并观察其毒副作用。 方法：14例非亲缘异基因干细胞移植采用静脉剂型白消安联合环磷酰胺预处理方案,18例亲缘异基因干细胞移植采用口服白消安联合环磷酰胺预处理方案,观察两组造血重建、植入率等疗效指标及胃肠道反应、口腔黏膜炎、出血性膀胱炎、肝功能损害、移植物抗宿主病等相关毒性指标。 结果与结论：两组患者植入率均为100%。静脉剂型组肝脏毒性、口腔黏膜炎发生率明显低于口服剂型组(14% vs. 67%,7% vs. 55%),差异均有显著性意义(P < 0.01),而胃肠道反应、出血性膀胱炎、造血重建、急性移植物抗宿主病、局限性移植物抗宿主病等方面差异均无显著性意义(P > 0.05)。结果可见静脉剂型白消安应用于非亲缘异基因造血干细胞移植预处理可获得满意疗效,且毒副反应少。     

Transfusion protocols in hematopoietic stem cell allogeneic transplantation]

Hematopoietic stem cell (HSC) allogeneic transplantation is now commonly used as a therapeutic tool in patients with certain types of hematologic malignancies. Such patients, on account of severe pre-graft conditioning regimens, present with severe marrow aplasia justifying specific transfusion care. Given a complex immunological situation (immediately after transplantation, co-existence of two cell populations with different immunohematological characteristics), transfusion protocols must rest on clear and well-defined recommendations. Recent transfusion recommendations in settings of HSC allogeneic transplantation have defined criteria for the choice of blood products (red blood cell concentrates, plasma and platelet concentrates) depending on recipient and graft immunohematological characteristics (minor/major/mixed ABO compatibility/incompatibility and time of transplantation). Transfusion instructions are summarized in a synthesis document entitled : "Instructions for transfusion following HSC allogeneic transplantation". This document specifies the immunohematological characteristics of blood products and various transfusion protocols (systematic irradiation, negative CMV, etc.). This document is used by the teams who distribute blood products, for selection purposes, as well as by the medical transfusion team when they perform ultimate pre-transfusion control steps.     

Effects of ABO incompatibility in allogeneic hematopoietic stem cell transplantation

IntroductionThe impact of ABO mismatch on outcomes following allo-HSCT remains controversial. In this study, our aim is to define the effect of ABO mismatch on post-transplant outcomes, engraftment kinetics and complications in a large cohort.Patients and methodsWe retrospectively identified 1000 patients who underwent allo-HSCT from either bone marrow or peripheral blood stem cells at our center between 1988 and 2016. P < 0.05 was considered statistically significant.ResultsFive hundred and ninety (59%) patient-donor pairs were ABO matched, 164 (16.4%) were ABO major mismatched (MM), 191 (19.1%) were ABO minor MM, and 55 (5.5%) were ABO bi-directionally MM. ABO matched pairs were more common in transplants from related donors (P < 0.001) and using bone marrow as a stem cell source (P < 0.001). In minor ABO MM transplantations, mild delayed hemolytic reaction occurred more frequently compared to major and bidirectional ABO MM transplantations (47% vs 35% and 18%, P < 0.001). Neutrophil engraftment was slightly delayed in ABO MM patient-donor pairs when compared ABO matched donor pairs according to median engraftment time in all group (167/410, 41% vs 204/590, 35%, P = 0.046). Pure red cell aplasia was diagnosed in 6 patients (1%). Higher risk of death was shown in ABO MM transplants compared to ABO matched transplants in overall survival (OS) analysis (HR:1.201, 95% CI:1.004–1.437, P = 0.045). The non-relapse mortality (P = 0.546) and cumulative incidences of acute graft versus host disease (aGVHD) and chronic (c) GVHD were comparable between ABO MM and ABO matched patient-donor pairs (for aGVHD, P = 0.235; for cGVHD, P = 0.137).ConclusionABO MM transplants were associated with decreased OS and slightly delayed neutrophil engraftment. NRM and the risk of GVHD were not related to ABO incompatibility.     

Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BO) is a late onset complication of allogeneic hematopoietic stem cell transplantation (HSCT), and treatment outcome is dismal if it does not respond to immunosuppressive therapy. A 21-year-old male diagnosed with acute myeloid leukemia received an allogeneic HSCT from human leukocyte antigen- identical sibling donor. Twenty one months after transplantation, he developed progressive dyspnea and was diagnosed BO. Despite standard immunosuppressive therapy, the patient rapidly progressed to respiratory failure and Novalung® interventional lung-assist membrane ventilator was applied in the intensive care unit. Three months after the diagnosis of BO, the patient underwent bilateral lung transplantation (LT) and was eventually able to wean from the ventilator and the Novalung®. Since the LT, the patient has been under a strict rehabilitation program in order to overcome a severe lower extremity weakness and muscle atrophy. Histologic findings of the explanted lungs confirmed the diagnosis of BO. Nine months after the LT, the patient showed no signs of rejection or infectious complications, but still required rehabilitation treatment. This is the first LT performed in a patient with BO after allogeneic HSCT in Korea. LT can be an effective therapy in terms of survival for patients with respiratory failure secondary to development of BO following HSCT.     

微卫星估价异基因外周血干细胞移植后嵌合状态

目的用检测5个四核苷酸重复序列了解异基因干细胞移植后嵌合状态以及预后的关系.方法PCR扩增120份正常人和10对移植供受者基因组DNA,据所得片段大小确定5个微卫星在人群中的多态性及移植后嵌合状态.结果各微卫星均发现7个以上等位基因(7～12)多态性,杂合度仅CSF1PO低于70%.移植患者中完全嵌合状态(CC)8例,1例死于GVHD;混合嵌合状态(MC)1例,死亡;受者型1例,死亡.结论5个四核苷酸重复序列点多态性可成功检测大多数嵌合状态.混合嵌合状态预后差.     

Erythrocyte transfusion practices after allogeneic hematopoietic stem cell transplantation]

Allogeneic peripheral blood hematopoietic stem cell transplantation is being evaluated in a randomized French study comparing the use of peripheral blood stem cells vs. bone marrow graft stem cells. In order to standardize immunohematological (IH) assessment and transfusion practices within our protocol, we made suggestions to 25 allo-transplantation French centers on the following elements: pre-inclusion IH assessment, IH exclusion criteria, transfusion rules, post-transplantation IH surveillance and treatment of hemolysis. The analysis of their responses to our suggestions led us to elaborate recommendations which were approved and implemented by the French Bone Marrow Transplantation Society (SFGM). These recommendations concern the transfusion practice in the general framework of allogeneic hematopoietic stem cell transplantation and can therefore be considered as referential.