造血干细胞移植后出血性膀胱炎的相关因素分析

目的观察造血干细胞移植后出血性膀胱炎的发病情况,探讨其发病危险因素和防治策略。方法回顾分析2006年1月～2009年12月期间88例因恶性血液病行造血干细胞移植患者的临床资料,治疗过程中均进行常规的出血性膀胱炎和移植物抗宿主病预防,分析移植后出血性膀胱炎发生的特点及相关因素。结果共14例患者发生移植后出血性膀胱炎(15.9%),其中5例人类白细胞抗原配型全相合,12例伴有其他部位移植物抗宿主病表现,发生巨细胞病毒感染阳性6人,EB病毒阳性5人。结论在采取充分的预防措施后,出血性膀胱炎仍有发生,而受者CMV感染是造血干细胞移后发生出血性膀胱炎的重要危险因素,而与其他各项因素均无显著相关性。     

Mycobacterial infections in adult recipients of allogeneic hematopoietic stem cell transplantation: A cohort study in a high endemic area

BackgroundMycobacterial infections are important and potentially life-threatening complications after organ transplantations. Notably, for the recipients of allogeneic hematopoietic stem cell transplantation (HSCT), there are a few supporting results to explore post-transplant mycobacterial infections. Taiwan is a high endemic area of the infection. We aim to investigate the incidence, risk factors, and survival of post-transplant mycobacterial infections, including mycobacterium tuberculosis (MTB) and non-tuberculous mycobacterium (NTM).MethodsWe included 422 adult patients undergoing allogeneic HSCT at an Asian tertiary medical center between January 2003 and December 2014. A total 26 subjects developed post-transplant mycobacterial infections. Risk factors, clinical features, and survival for post-transplant mycobacterial infections were collected and analyzed.ResultsPost-transplant mycobacterial infections occurred in 26 (6.2%) of 422 HSCT patients. Two-year cumulative incidences in MTB and NTM were 1.4% and 5.4%. In the multivariate analysis, being age >45 years (adjusted HR 2.21, 95% CI 1.01–4.83) and extensive chronic graft-versus-host disease (cGVHD) (adjusted HR 4.95, 95% CI 2.14–11.46) were identified as independent risk factors of infections. There was a trend as a risk factors in relapsed patients (P = 0.088). For patients with cGVHD, there was a significant difference of post-transplant survival between mycobacterial infections and none (P = 0.036). Pneumonia contributed most to mortality (n = 11, 42.3%).ConclusionMycobacterial infections are worth to note in a high endemic area. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection and treatment of infections.     

异基因造血干细胞移植CD94分子在T细胞高表达的意义初探

目的检测CD94分子在T细胞表达的水平,同时探讨在异基因造血干细胞移植(HSCT)中发生移植物抗宿主病(GVHD)患者CD94分子在T细胞表达的意义。方法HSCT治疗高危白血病和遗传性溶血性贫血成功植入的儿童患者,其中同胞脐血移植(UCBT)10例,非血缘相关UCBT1例,异基因外周血造血干细胞移植(alloPBSCT)5例,在移植前后发生GVHD时采用流式细胞仪检测和比较外周血中CD94的表达,并与正常外周血水平比较。结果CD94主要表达于CD3+CD8+T细胞,正常情况下外周血和脐血T细胞表达率低于10%,其中CD4+细胞几乎不表达,低于2%。但在UCBT或alloPBSCT后CD94在CD4+T细胞和CD8+T细胞均明显增高。3例UCBT无GVHD,其余均发生了ⅠⅣ0急性GVHD。急性GVHD发生时CD4+CD94+和CD8+CD94+T细胞表达明显升高。结论异基因造血干细胞移植后发生GVHD时,T细胞高表达CD94,可能是在同种抗原的刺激下机体自我保护的结果。     

树突状细胞和造血干细胞移植的研究进展

树突状细胞(DC)是功能最强的抗原递呈细胞(APC),在移植免疫中,DC启动免疫排斥还是维持免疫耐受取决它们的起源以及成熟状态,成熟DC启动免疫排斥及移植物抗宿主病(GVHD)反应,未成熟(iDC)及淋巴样DC诱导免疫耐受。造血干细胞移植(HSCT)中,可以通过调控不同来源、不同分化状态的DC来预防和治疗移植物抗宿主病(GVHD),促进造血干细胞的植入。     

Adoptive precursor cell therapy to enhance immune reconstitution after hematopoietic stem cell transplantation

Strategies to enhance post-transplant immune reconstitution without aggravating graft-vs-host disease (GVHD) can improve the outcome of allogeneic hematopoietic stem cell transplantation. Recent preclinical studies demonstrated that the use of T cell depleted allografts supplemented with committed progenitor cells (vs stem cells only) allows enhanced immune reconstitution of specific hematopoietic lineages including myeloid, B, T, and natural killer lineages in the absence of GVHD. This novel adoptive therapy resulted in significantly improved resistance to microbial pathogens and could, in some cases, even mediate tumor immunity. Clinical protocols using adoptive transfer of committed hematopoietic progenitor cells are currently being evaluated.     

基质细胞与造血干细胞移植后的造血重建

造血干细胞移植作为造血损伤修复及血液病治疗的主要手段已日益受到重视。受体的造血系统重建取决于两个条件：一是造血干细胞的质量和数量,二是造血微环境的质量。１９７７年,Ｄｅｘｔｅｒ用小鼠骨髓细胞进行长期培养,发现造血细胞只有附着于一种被称为基质细胞的集落上,才能增殖。而后 Ｍａｕｃｈ等［１］继而在人骨髓细胞长期培养的实验中证实了这一点。可以认为造血干细胞在分化增殖需要有一个特殊的环境,即造血微环境。基质细胞是造血微环境的主要成分,具有支持造血的作用。 一、基质细胞 造血微环境（ｈｅｍａｔｏｐｏｉｅｔｉ…     

造血干细胞移植治疗系统性红斑狼疮的进展

系统性红斑狼疮是一种病因未明的自身免疫性疾病,基本上由自身抗体和免疫复合物介导致病.随着医学在基因水平上不断发展,对于重症SLE不能耐受传统疗法,HSCT目前已是公认的潜在治疗手段之一.从报道HSCT治疗严重AID至今,大约有20个国家的700个患者接受了临床Ⅰ/Ⅱ试验.研究认为,大剂量免疫抑制和移植后免疫重建可能是使SLE缓解的机制.经过10年的临床试验,国内对HSCT治疗手段不断成熟,以北京协和医院为首.虽有明显改善SLE病情,但随诊时期不长,仍存在着许多需要进一步解决的问题,HSCT给予那些难治的其他疗法无效的患者提供了"补救疗法",是否更有效,仍需要进一步进行随机化控制实验.     

不同预处理移植后树突状细胞早期重建及与移植物中CD34+细胞相关性分析

目的：比较不同预处理异基因造血干细胞移植（allo-HSCT）后早期树突状细胞（DCs）亚群重建情况，以及移植物中CD34^＋细胞是否影响移植后早期DCs亚群重建。方法：采用三色流式细胞仪动态检测不同预处理移植后早期外周血树突状细胞亚群DC1、DC2水平。结果：移植后早期清髓性移植患者体内DCs亚群数量非常低，常规移植组移植后14天与半相合移植组相比，DC1、DC2均无统计学意义（P〉0．05）。非清髓性移植组（NST）DC1、DC2高于清髓性移植组，两者相比具有统计学意义（P〈0．05）。在30天和60天，所有组DC1、DC2略有波动，但是幅度不大。以输入的CD34^＋细胞数平均分为三组，三组患者DC1、DC2移植后14、30和60天均无统计学意义（P〉0．05）。结论：NST后患者早期DCs重建较清髓性干细胞移植患者早，而常规移植和半相合移植早期DCs重建较慢，二者无差别。移植物中的CD34^＋细胞不影响移植后早期DCs亚群重建。     

抗CD20单抗在致敏受者造血干细胞移植中应用的实验研究

目的： 寻找促进异基因造血干细胞在致敏受者植入的策略研究,探讨抗CD20单抗在致敏受者造血干细胞移植的作用。方法：分别于移植前第14 d及第7 d予BALB/c小鼠输注C57BL/6小鼠的脾细胞建立致敏模型。实验组于移植前第11 d经尾静脉输注抗CD20单抗（美罗华）2 mg/mouse,对照组于移植前第11 d予输注RPMI-1640培养液 0.2 mL/mouse。于第0 d（移植当天）取部分小鼠分离得血清及脾细胞,并检测供者反应性抗体及CD19＋B细胞;部分小鼠予［60Co］致死量照射,4 h后予1×107 C57BL/6小鼠骨髓细胞进行移植,观察生存情况及血常规恢复情况。结果：实验组与对照组血清细胞毒性指数分别为（37.00±3.46）％和（51.80±3.49）％,差异显著（P<0.01）;2组的脾细胞CD19＋B细胞百分比分别为（17.32±3.02）％和（34.26±2.87）％,差异显著（P<0.01）。照射移植后2组受者均于14 d左右全部死亡,生存中位数分别为第13 d及第11 d,Log-rank检验2组间的差别无显著（P>0.05）。濒死动物血常规结果示三系减少,提示受者死于造血衰竭。结论：抗CD20单抗能杀伤受者B细胞,降低致敏程度,但实验中该单抗并不能有效促进异基因造血干细胞在致敏受者的植入。     

Reconstitution of the immune system after hematopoietic stem cell transplantation in humans

Hematopoietic stem cell transplantation is associated with a severe immune deficiency. As a result, the patient is at high risk of infections. Innate immunity, including epithelial barriers, monocytes, granulocytes, and NK cells recovers within weeks after transplantation. By contrast, adaptive immunity recovers much slower. B- and T-cell counts normalize during the first months after transplantation, but in particular, T-cell immunity may remain impaired for years. During the last decade, much of the underlying mechanisms have been identified. These insights may provide new therapies to accelerate recovery.     

异基因造血干细胞移植后的相关并发症及危险因素

背景：有效预防和治疗异基因造血干细胞移植后并发症是提高患者存活率的重要因素。 目的：分析异基因造血干细胞移植后相关并发症的发生和危险因素。 方法：应用文献检索的方法获取异基因造血干细胞移植后相关并发症研究的文献,对符合研究标准的文献进行深入的数据分析,文章选取异基因造血干细胞移植后极易发生的并发症进行分析,如肺部并发症、真菌性败血症、巨细胞病毒感染以及中枢神经系统并发症等。 结果与结论：异基因造血干细胞移植后易出现肺部并发症,而且死亡率较高,肺部并发症的发病机制可能与移植物抗宿主病和巨细胞病毒抗原血症相关。异基因造血干细胞移植后真菌性败血症病原菌以假丝酵母菌属为主,死亡率较高,应二级预防性和早期经验性抗真菌治疗。更昔洛韦、膦甲酸钠对异基因造血干细胞移植后巨细胞病毒感染的治疗有效。中枢神经系统并发症在异基因造血干细胞移植后发生率较低,但在治疗过程也不容忽视。异基因造血干细胞移植后相关并发症的发生与多种危险因素有关,在临床治疗过程中要对相关因素采取预防措施,减少并发症的发生,提高患者的存活率。     

The clinical course of COVID-19 in hematopoietic stem cell transplantation (HSCT) recipients

Background/aim The disease caused by SARS-CoV-2 was named as COVID-19. There is as yet insufficient information about the effects of HSCT on the clinical course of COVID-19. In the present study, we aimed to investigate the clinical course of COVID-19 in patients who had undergone HSCT. Materials and methods We analyzed baseline characteristics, clinical course and findings of COVID-19, hospitalization and death rates, overall survival, and case fatality rates of HSCT recipients diagnosed with COVID-19 retrospectively. Results 57.6% of the patients underwent AHSCT, and 42.4% underwent allo-HSCT. 60.6%, 27.3%, and 12.1% of the patients had mild, moderate, and severe COVID-19 or critical illness, respectively. Overall, 45.5% were hospitalized, 12.1% required intensive care, and 9.1% necessitated invasive mechanical ventilation. The total CFR was 9.1% in HSCT recipients, 22.2% in patients with active hematologic malignancy, and 4.2% in patients without active hematologic malignancy. Conclusion It can be concluded that mortality of HSCT recipients is lower in patients whose primary disease is in remission compared to ones that are not in remission. Further studies with larger group patients are needed in order to delineate the effects of COVID-19 on HSCT patients.     

Therapeutic applications of non-myeloablative hematopoietic stem cell transplantation in malignant disease

Allogeneic hematopoietic stem cell transplantation (HSCT) currently provides the only chance of curative therapy for many patients with hematological malignancies. Owing to the excess morbidity and mortality observed in less robust patients, this approach has traditionally been limited to younger patients without significant medical co-morbidities. Given the age profiles of patients with candidate hematological malignancies, a majority of patients are therefore ineligible for myeloablative therapy. Over the past few years the ability to achieve hematopoietic stem cell engraftment using immunosuppressive but non-myeloablative conditioning regimens has made it possible to consider a much broader group of patients for allogeneic HSCT. The discovery that the hematopoietic graft itself can contribute to the eradication of malignant cells through a graft-versus-malignancy (GVM) effect, independent of the conditioning regimen, has led to investigation of reduced intensity conditioning regimens for a variety of malignant diseases. Over the past few years there has been a dramatic increase in the number of patients undergoing reduced intensity conditioning for both malignant and nonmalignant conditions. This review will focus only on the use of such therapy for malignant disease.     

造血干细胞移植治疗自身免疫性疾病

自从1995年造血干细胞移植（HSCT）应用于难治复发性自身免疫性疾病（AID）的治疗以来,取得了令人鼓舞的疗效,最近已经进入Ⅲ期临床试验阶段。AID可能是一种造血干细胞异常所致疾病,本文主要就自体或异体HSCT治疗AID的原理及自体HSCT治疗几种主要AID的临床试验结果做一综述。     

FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

A prolonged period of T‐cell recovery is the major challenge in hematopoietic stem cell transplantation (HSCT). Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T‐cell generation. However, TECs undergo degeneration over time. FOXN1 plays a critical role in TEC development and is required to maintain adult TECs for thymopoiesis. To investigate the potential application of FOXN1, we have cloned and expressed recombinant FOXN1 protein (rFOXN1) that was fused with cell‐penetrating peptides. We show here that the rFOXN1 protein can translocate from the cell surface into the cytoplasm and nucleus. Administration of rFOXN1 into both congenic and allogeneic HSCT recipient mice increased the number of TECs, resulting in enhanced thymopoiesis that led to an increased number of functional T cells in the periphery. The increased number of TECs is due to the enhanced survival and proliferation of TECs. Our results suggest that rFOXN1 has the potential to be used in enhancing T‐cell regeneration in patients following HSCT.     

Space-time considerations for hematopoietic stem cell transplantation

The mammalian blood system contains a multitude of distinct mature cell lineages adapted to serving diverse functional roles. Mutations that abrogate the development or function of one or more of these lineages can lead to profound adverse consequences, such as immunodeficiency, autoimmunity, or anemia. Replacement of hematopoietic stem cells (HSC) that carry such mutations with HSC from a healthy donor can reverse such disorders, but because the risks associated with the procedure are often more serious than the blood disorders themselves, bone marrow transplantation is generally not used to treat a number of relatively common inherited blood diseases. Aside from a number of other problems, risks associated with cytoreductive treatments that create "space" for donor HSC, and the slow kinetics with which immune competence is restored following transplantation hamper progress. This review will focus on how recent studies using experimental model systems may direct future efforts to implement routine use of HSC transplantation to cure inherited blood disorders.     

Letermovir prophylaxis for cytomegalovirus reactivation in children who underwent hematopoietic stem cell transplantation: A single-institute experience in Taiwan

From January 2019 to May 2021, 11 children underwent allogeneic stem cell transplantation at our institute. Four of them received letermovir for cytomegalovirus prophylaxis. Three children, none of whom received prophylaxis, experienced cytomegalovirus reactivation. Letermovir is a promising medication for use in cytomegalovirus prophylaxis in children. Further studies are warranted.     

Morphine consumption is associated with systemic inflammation in children undergoing allogeneic hematopoietic stem cell transplantation

Background: The majority of children undergoing allogenic hematopoietic stem cell transplantation (HSCT) experience severe pain due to chemotherapy-induced gastrointestinal toxicity. Inter-individual differences in pain perceived and opioid consumption remain unexplained, limiting the possibility for individualized pain control. The aim of this study was to investigate the associations between opioid consumption and markers of gastrointestinal toxicity (plasma citrulline) and systemic inflammation (plasma CRP and IL-6) in these patients.

Methods: We retrospectively included 38 children undergoing HSCT in Denmark in 2010–2012. Opioids doses on days 0–21 post-HSCT were registered as intravenous morphine equivalents (MEs). CRP was measured daily on days 0–21. IL-6 was measured on day 7. Citrulline was measured before conditioning, on days 7 and 21.

Results: Out of 38 children, 37 (97%) received opioids during days 0–21. CRP level and ME dose peaked on days 9–10 while citrulline level reached a nadir on day 7 indicating maximum enterocyte loss. CRP was associated with ME dose, with an estimated increase of 0.030?mg/kg (95% CI 0.024–0.035) in ME for a 50% increase in CRP level on the same day (p?<?.001). IL-6 was correlated with ME on day 7 (rho = 0.55, p?=?.002). Citrulline did not correlate with ME.

Conclusions: Opioid consumption in the early post-HSCT period is associated with the degree of chemotherapy-induced systemic inflammation and not with the extent of enterocyte loss. These findings contribute to our understanding of mucositis-related pain and may be of interest for future studies on therapeutic strategies.     

Key factors in experimental mouse hematopoietic stem cell transplantation

The first mouse model of hematopoietic stem cell transplantation (HSCT) was developed more than 50 years ago. HSCT is currently being widely used in a broad range of research areas, which include studies of the engraftment process, the pathogenesis of graft-versus-host disease and possible ways of its treatment and prophylaxis, attempts to use the graft-versus-leukemia/tumor effect in treating hematological and oncological malignancies, cancer vaccine development, induction of transplanted organ tolerance, and gene therapy. However, although this model is widely distributed, many laboratories use different protocols for the procedure. There are a number of papers discussing different HSCT protocols in clinical work, but no articles summarizing mouse laboratory models are available. This review attempts to bring together different details about HSCT in the mouse model, such as the types of transplantation, possible pretreatment regimens and their combinations, methods and sources of graft harvesting and preparation for the transplantation procedure, the influence of graft cell dose and content on the engraftment process, the transplantation method itself, possible complications, symptoms and techniques of their prophylaxis or treatment, as well as follow-up and engraftment assessment. We have also tried to reflect current knowledge of the biology of the engraftment.