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目的探讨异基因骨髓移植小鼠体内调节性T细胞（Treg）、NK细胞以及与其功能相关的细胞因子白介素-10（IL-10）、转化生长因子（TGF-β）、穿孔素与急性移植物抗宿主病（aGVHD）的关系。方法建立H-2完全不合的C57BL/6→BALB/c纯种小鼠间异基因骨髓移植后发生aGVHD模型。流式细胞仪检测移植后存活的aGVHD小鼠脾脏CD4＋CD25＋Treg细胞和NK-1.1＋NK细胞的比例;ELISA方法检测环孢素A干预aGVHD小鼠血清IL-10、TGF-β和穿孔素的水平,以正常的C57BL/6小鼠为对照。结果与正常小鼠相比,移植后发生aGVHD小鼠体内Treg细胞比例下降（3.6%vs.1.55%）,NK细胞比例上升（3.3%vs.11.5%）;环孢素A治疗aGVHD组小鼠,与未干预组相比,血清IL-10水平明显上升[（125.79±0.27）pg/mL vs.（103.09±3.27）pg/mL,P〈0.01],TGF-β水平上升但无统计学差异[（252.05±7.84）pg/mL vs.（241.61±15.41）pg/mL,P〉0.05],穿孔素水平明显上升[（186.97±4.68）pg/mLvs.（144.35±14.42）pg/mL,P〈0.01]。结论 （1）小鼠移植后发生aGVHD与Treg细胞比例下降有关,Treg功能相关的细胞因子IL-10、TGF-β参与环孢素A介导的免疫抑制治疗;（2）NK细胞参与异基因骨髓移植后aGVHD的发生过程,穿孔素的水平上升与抑制aGVHD有关。

目的：观察非血缘异基因造血干细胞移植治疗白血病的临床疗效及并发症。方法回顾性分析21例非血缘异基因造血干细胞移植的恶性血液病患者临床资料,其中19例为外周血造血干细胞移植,1例为骨髓移植,1例为脐血移植。HLA 全相合8例,HLA 不全相合13例。回输单个核细胞（MNC）中位数9.078×108/kg,CD34＋细胞中位数4.62×106/kg。10例患者采用 BuCy 方案预处理,9例采用改良的 BuCy2方案预处理,1例采用非清髓的 BuCy＋氟达拉滨的方案,1例采用 TBI＋VP-16＋CTX＋meCCNU 预处理。预防移植物抗宿主病方案,其中20例采用短程甲氨蝶呤＋环孢素 A＋霉酚酸酯＋抗胸腺细胞免疫球蛋白的四联方案,1例脐血移植患者采用短程甲氨蝶呤＋环孢素 A ＋抗胸腺细胞免疫球蛋白。术后观察受者的造血重建、并发症以及预后情况。采用低剂量肝素＋前列腺素 E1＋丹参注射液预防肝静脉闭塞病（VOD）。结果除 1例患者于空髓期死于颅内出血,其余20例患者均获造血重建。高剂量组MNC 及 CD34＋细胞较低剂量组中位重建时间平均缩短1 d。预处理中出现高热、寒战、胃肠道副反应、肝脏损伤及口腔黏膜炎等副反应,均给予对症处理后好转。HLA 不合者较 HLA 全相合者移植后移植物抗宿主病（GVHD）发生率高,差异有统计学意义。9例患者出现 aGVHD（Ⅰ度 3例,Ⅱ度4例,Ⅲ度2例）；9例出现 cGVHD,表现为皮肤及肝脏受损,经有效治疗后好转。术后100 d 内18例受者出现细菌或真菌感染,以上呼吸道感染为主,7例发生巨细胞病毒感染,2例出现 EB 病毒血症,1例出现尿 BK 病毒感染。1例患者因 VOD 死亡,其余患者均未发生 VOD。5例发生Ⅱ级至Ⅲ级出血性膀胱炎,经治疗后均好转。受者总的中位生存时间为24月（136 d~9年）,1年及3年总生存率分别为85.2%和63.9%,无病生存率分别为81.0%和23.8%,无复发生存率为71.4%和14.3%。结论非血缘异基因造血干细胞移植是治疗白血病的有效方法；BuCy 及改良 BuCy2的预处理方案均安全有效,毒性反应可逆、可耐受；高剂量 MNC 及 CD34＋细胞数组造血重建时间较低剂量组缩短；HLA 不全相合者移植后 GVHD 发生率较 HLA 全相合者增高；低剂量肝素＋前列腺素 E1＋丹参注射液可有效预防 VOD。

目的观察亲代间单倍体相合造血干细胞移植治疗血液病的临床疗效。方法第三军医大学新桥医院血液科自2007年7月-2011年l月，对45例患者实施父母供子女的亲代间单倍体相合造血干细胞移植，观察其临床疗效及并发症。结果43例患者造血重建成功，2例患者植入失败。移植物抗宿主病（GVHD）发生率为62．2％，其中急性GVHD发生率为40．0％，慢性GVHD发生率为22．2％。与母亲作为供者相比，父亲作为供者时患者GVHD的发生率较低。GVHD的发生率与供者年龄、HLA配型相合位点数目有关。移植后并发的感染中以血源性巨细胞病毒感染和肺部感染为多。随访6个月～4年，移植成功的43例患者中共死亡6例，主要死因为感染和原始疾病复发，患者存活率86．7％。7例患者采用联合脐血移植，与单纯采用亲代间单倍体造血干细胞移植者相比，其造血重建时间提前，GVHD发生率占总发生率的7．14％。结论亲代间单倍体造血干细胞移植对治疗血液病有效，应选择HLA配型相合位点数目较多、男性、年轻供者。亲代间单倍体相合造血干细胞移植联合脐血移植，造血重建较快、GVHD发生率较低。

目的通过小鼠混合骨髓移植模型，将同基因和半相合异基因小鼠骨髓细胞和不同比例脾细胞混合移植给受鼠，探讨诱导持久稳定嵌合体、减轻严重移植物抗宿主病（GVHD）的方法。方法受鼠^60Co全身照射，混合输入同基因和半相合异基因供鼠骨髓，同时将两者脾细胞按不同比例混合回输。测定嵌合体形成，观察GVHD表现及病理学改变，监测移植鼠生存率。结果小鼠移植后全部存活超过90d，半相合异基因小鼠脾细胞输注剂量和比例对嵌合体形成的水平和嵌合状态的稳定性有显著影响。信论调整半相合异基因与同基因小鼠脾细胞输注剂量和比例对诱导异体持久植活、避免严重的GVHD的出现具有实际意义。

FOXP3＋ regulatory T （Treg） cells are critical in maintaining immune tolerance and homeostasis of the immune system. The molecular mechanisms underlying the stability, plasticity and functional activity of Treg cells have been much studied in recent years. Here, we summarize these intriguing findings, and provide insight into their potential use or manipulation during Treg cell therapy for the treatment of autoimmune diseases, graft-versus-host disease （GVHD） and cancer.

Antithymocyte globulin （ATG） is often included in the conditioning regimen to prevent graft vs. host disease in allogeneic hematopoietic stem cell （HSC） transplantation. However, because ATG contains antibodies targeting a wide range of antigens on human cells, its potential off-target effects remain a concern. Here, we explored this question in humanized mice that permit the analysis of human cell depletion in tissues. We showed that ATG binds to almost all lineages of human hematopoietic cells including HSCs, and accordingly it is capable of depleting almost all human hematopoietic cells. Interestingly, the efficacy of ATG was highly variable depending on the tissue of residence, with human cells in bone marrow significantly less susceptible than those in the blood and spleen. Recovery of multilineage human lymphohematopoietic reconstitution in humanized mice that received ATG 3 weeks after HSC transplantation indicates that ATG had a minimal effect on human HSCs that have settled in bone marrow niches. However, efficient human HSC depletion and engraftment failure were seen in mice receiving ATG at the time of transplantation. Our data indicate that the efficacy of ATG is tissue-dependent, and suggest a potential risk of impairing donor hematopoietic engraftment when ATG is used in preparative conditioning regimens.

Graft-versus-host disease （GVHD） is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 （TLR4）, which is a major receptor for bacterial lipopolysaccharides （LPS）, in the development of acute GVHD, we used a TLR4-knockout （TLR4-/-） mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4-/- mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type （TLR4＋/＋） mice. In addition, histopathological analyses revealed that in TLR4-/-→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4＋/＋, TLR4-/- mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4-/- mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 （Th 1） development was obviously attenuated compared with TLR4＋/＋ mice dendritic cells, and the levels of interferon-T （IFN-γ） and IL-IO, Th2-cell specific cytokines, were significantly higher in the serum of TLR4-/-→BALB/c than in TLR4＋/＋→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.

Regulatory T cells （Tregs） comprise a subset of CD4＋ T lymphocytes that holds promise as immunotherapy for inflammat- ory disease states including autoimmune disorders, solid organ allograft rejection, graft-versus-host disease, and acute inflam- matory conditions. However, limited availability of Treg numbers restricts their usefulness in cell transfer applications, particularly as patients may need multiple infusions for chronic diseases.

FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an SIPl-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an SIPl-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

In allogeneic stem cell transplantation （SCT）, natural killer （NK） cells lacking their cognate inhibitory ligand can induce graft-versus-leukemia responses, without the induction of severe graft-versus-host disease （GVHD）. This feature can be exploited for cellular immunotherapy. In this study, we examined selective expansion of NK cell subsets expressing distinct killer immunoglobulin-like receptors （KIRs） within the whole human peripheral blood NK cell population, in the presence of HLA-Cw3 （C1） or Cw4 （C2） transfected K562 stimulator cells. Coculture of KIR＋ NK cells with C1 or C2 positive K562 cells, in the presence of IL-2＋ IL-15, triggered the outgrowth of NK cells that missed their cognate ligand. This resulted in an increased frequency of alloreactive KIR＋ NK cells within the whole NK cell population. Also, after preculture with K562 cells lacking their cognate ligand, we observed that this alloreactive NK population revealed higher numbers of CD107~ cells when cocultured with the relevant K562 HLA-C transfected target cells, as compared to coculture with untransfected K562 cells. This enhanced reactivity was confirmed using primary leukemic cells as target. This study demonstrates that HLA class I expression can mediate the skewing of the NK cell repertoire and enrich the population for cells with enhanced alloreactivity towards leukemic target cells. This feature may support future clinical applications of NK cell-based immunotherapy.