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1.
目的: 选择性去除骨髓移植物中异基因反应性淋巴细胞,特异性抑制移植物抗宿主病(graft versus host disease, GVHD)并保留移植物的抗白血病(graft versus leukemia, GVL)作用。方法:分别把未经处理的、溶T淋巴细胞处理的和以FasL基因修饰树突状细胞(FasLDC)处理的  相似文献   

2.
树突状细胞(Dendritic cells,DCs)是体内惟一能使静息T细胞对新抗原致敏的抗原递呈细胞(APCs),在免疫反应中起着触发作用.近年来,关于DCs与造血干细胞移植(HSCT)后移植物抗宿主病(GVHD)的发生及移植后免疫耐受的诱导成为研究的热点,本文就此方面的研究进展进行综述.  相似文献   

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NK细胞与异基因骨髓移植   总被引:3,自引:0,他引:3  
近年来研究发现,自然杀伤细胞在异基因骨髓移植中也起飞丰独特的作用,宿主的静息状态自然杀伤细胞能排斥异基因骨髓细胞;而供者的活化自然杀菌细胞输注宿主体内能促进骨髓植入和造血重建,还能够预防异基因骨髓移植的严重并发症-移植物抗宿主病,并增强抗肿瘤效应。本文综述了这些方面的研究近况和新进展。  相似文献   

6.
 异基因干细胞移植后树突状细胞(DC)恢复的特点是移植后DC细胞亚群均较移植前水平低,单核细胞样DC在移植后300 ~ 400 d可以恢复正常水平,浆细胞样DC恢复很慢。它的重建受到粒细胞刺激因子、前炎性的细胞因子及间充质干细胞的影响,与异基因移植CD+34剂量无关。通过分析DC与移植物抗宿主病关系的分析,发现低数量的DC会导致高的GVHD的发生率,并有学者对这种现象的机制进行了解释。就移植后树突状细胞、亚群重建规律及其与急性移植物抗宿主病的关系的主题进行综述。  相似文献   

7.
目的: 选择性去除骨髓移植物中异基因反应性淋巴细胞,特异性抑制移植物抗宿主病(GVHD).方法: 用携带有FasL基因的重组腺病毒转染Balb/c小鼠来源的树突状细胞(dendritic cells, DC),并与C57BL/6小鼠骨髓细胞移植物共培养,把经过这种处理的骨髓细胞移植物移植给Balb/c受体小鼠(C57BL/6→Balb/c小鼠GVHD 模型 ,H-2b→H-2d),然后观察、比较各组GVHD表现.结果: 致死剂量照射的受体鼠在接受经FasL-DC处理的供体骨髓细胞移植后,没有出现明显的GVHD表现,生存期显著延长,3个月时生存率80%以上.但对照组2周后均出现了明显的GVHD症状,腹泻、脱毛和靶组织淋巴细胞浸润等,生存期没有超过30 d.结论: 转染FasL基因的DC可有效去除骨髓移植物中异基因反应性T淋巴细胞,移植用这种方法处理过的骨髓,能够有效抑制GVHD的发生.  相似文献   

8.
目的:选择性去除骨髓移植物中异基因反应性淋巴细胞,诱导异基因特异性低反应性.方法:用携带有FasL基因的重组腺病毒转染BALB/c小鼠来源的DC,并与C57BL/6小鼠脾淋巴细胞共培养,通过混合淋巴细胞培养等方法检测异基因特异性低反应性.结果:转染FasL基因的DC诱导了对BALB/c异基因反应性T淋巴细胞凋亡,2次混合淋巴细胞反应显著降低,但并没有抑制针对第三方的反应.结论:转染FasL基因的DC体外可有效去除骨髓移植物中异基因反应性T淋巴细胞,移植用这种方法处理过的骨髓,有希望在抑制GVHD的同时,不影响移植物抗肿瘤复发和抗感染的功能.  相似文献   

9.
同种异基因Th2细胞移植后抗白血病效应研究   总被引:1,自引:0,他引:1  
移植物抗白血病(GVL)效应是同种异体免疫细胞清除白血病细胞和抗复发的重要手段,与T细胞有着密切的关系.骨髓移植后,供者T细胞可被同种异体抗原识别激活并直接攻击受者组织,或者通过分泌细胞因子的“瀑布效应”加重对受者的损伤,这种损伤对象为白血病细胞时就表现为GVL作用.在GVL效应中,供者来源的CD4~ 细胞是重要的调节细胞.已知CD4~ 细胞依其产生的细胞因子成份分为Th1和Th2细胞,Th2细胞可以通过其分泌的IL-4调控Th1及M_(?)细胞功能,减少GVHD致病因子(IL-1,IL-2,IL-12,TNF,IFN-γ,NO)的产生.本文以荷EL9611细胞的红白血病小鼠模型为对象,采用体外诱导的Th2细胞进行异基因骨髓移植,探讨Th2细胞移植是否保留移植物抗白血病效应.我们  相似文献   

10.
目的:研究γδT细胞的体外生存期,抗白血病活性及可能引起的GVHD,为将来自体及异体移植后输注γδT细胞诱导GVL作前期基础研究。方法:对移植患者采集物用GM-CSF+IL-4进行培养,使其分化和扩增为DC;然后用DC和细胞因子IL-2刺激其CD4^ T细胞扩增后,协同DC共同刺激γδT细胞扩增,进而用MTT比色法和CFU-GM集落培养研究其功能。结果:γδT细胞能在体外长期大量扩增。扩增的γδT细胞对多咱白血病细胞株具有杀伤作用,而对自体及异体CFU-GM集落形成能力无显著影响。结论:γδT细胞可望用于造血干细胞移植后的过继免疫治疗,值得进一步做有关临床研究。  相似文献   

11.
Salivary glands are uncommonly involved in leukemia. Moreover, isolated leukemic relapse in salivary glands is an extremely rare event. We report a young adult male with acute lymphoblastic leukemia who presented with an isolated extramedullary relapse of his leukemia in a left sided submandibular salivary gland just before his planned allogeneic bone marrow transplant. The patient underwent a wide surgical excision of the involved salivary gland then he received a conditioning protocol composed of total body irradiation and cyclophosphamide followed by a successful allograft.  相似文献   

12.
目的:探讨小鼠树突状细胞(dendritic cells,DCs)转染吲哚胺2,3-二氧化酶(indolamine 2,3-dioxygenase,IDO)基因后对移植物抗宿主病(graft versus host disease,GVHD)的抑制作用。方法:用携带IDO基因的重组腺病毒感染BALB/c小鼠来源的树突状细胞,后者与C57BL/6小鼠骨髓移植物共培养,将经过处理的骨髓移植给BALB/c小鼠(C57BL/6→BALB/c小鼠GVHD模型,H-2~h→H-2~d),观察、比较各组GVHD表现(包括GVHD评分、生存期、病理学改变),并行嵌合体检测及观察混合淋巴细胞反应(mixed lymphocyte reaction,MLR)。结果:致死剂量照射的受体小鼠接受经IDO处理的骨髓移植(bone marrow transplantation,BMT)后,未出现明显的GVHD反应,生存期显著延长,3个月时生存率大于80%;对照组均在移植后2周左右出现明显的GVHD表现,生存期未超过1个月。IDO-DC治疗组未出现明显的组织病理学损害;3个月时IDO-DC治疗组仍然保持比较高的嵌合;IDO-DC组的T细胞对C57BL/6、BALB/c淋巴细胞的反应性与对C3H淋巴细胞反应性相比显著降低(P<0.05)。结论:经IDO基因修饰的DCs可以选择性去除骨髓移植物中异基因反应性T细胞,从而特异性地抑制GVHD并能及早地免疫重建。  相似文献   

13.
Summary In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancer in some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B 16 melanoma in a murine model. This combination generated cells with MHC-unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the nontransplant setting to induce an antitumor immune response following cytoreductive chemotherapy.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.  相似文献   

14.
MHC半相合脾加骨髓细胞诱发H22荷瘤鼠的抗肿瘤效应   总被引:3,自引:1,他引:3  
目的:观察MHC半相合脾加骨髓细胞移植抗小鼠H22实体瘤的效果。方法:以皮下接种H22肝癌细胞的BALB/c×C57BL/6杂交F1代雌性小鼠为受鼠,以健康雌性F1、雄性C57BL/6、雄性C3H小鼠为MHC全相合、半相合、不相合供鼠,观察移植后的抑瘤情况;观察供鼠细胞经~(60)Co照射的MHC半相合移植对WBC、生化和嵌合体的影响;比较供鼠细胞经与不经~(60)Co照射的MHC半相合移植的GVHD情况。结果:供鼠细胞经/不经~(60)Co照射的MHC半相合移植小鼠的肿瘤明显较小,与单纯化疗未进行移植者比较,差异具有统计学意义(P<0.05);但受鼠未经化疗预处理的MHC半相合细胞输注没有出现抗肿瘤效应;供鼠细胞经7.5 Gy ~(60)Co照射的MHC半相合移植能明显降低GVHD反应,且对外周血白细胞、生化无不良影响。结论:经7.5 Gy~(60)Co照射的MHC半相合脾加骨髓细胞移植能对H22肝癌细胞产生移植物抗肿瘤效应并降低GVHD反应。  相似文献   

15.
The graft-versus-tumor (GVT) effect that occurs following allogeneic bone marrow transplantation (BMT) and donor lymphocyte infusion (DLI) is currently being subjected to intensive investigation because of clinical evidence for GVT efficacy against leukemia. In this report, we investigate the efficacy and molecular mechanisms of GVT against solid tumors, using a modification of the mouse parent-to-F1 BMT model. Mouse Colon26 cells in which tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor expression was stably knocked down were transplanted to investigate the role of the TRAIL-TRAIL receptor system in the GVT effect. In addition, Fas ligand-(FasL) deficient mice on a C57BL6 (B6) background were used as donors, to determine the significance of the Fas-FasL system for the antitumor effect. The group that received B6 DLI followed by preconditioning with 950 rad irradiation underwent tumor reduction associated with the induction of IFN-gamma, TRAIL and tumor-cell apoptosis. In vitro cultured Colon26 cells were resistant to TRAIL but susceptible to the combination of IFN-gamma and TRAIL in a TRAIL-dose-dependent manner. The infusion of lymphocytes from FasL-defective donors reduced the tumor progression, although efficacy was decreased in the TRAIL receptor knockdown tumors but not in wild-type ones, compared with infusion of B6-derived lymphocytes. The findings indicate that GVT activity against subcutaneous colon tumors is efficiently induced by preconditioning with irradiation and allogeneic DLI, and that TRAIL and IFN-gamma act cooperatively in the antitumor effect.  相似文献   

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目的〖HT5"SS〗: 探讨吲哚胺2,3双加氧酶(indoleamine 2,3 dioxygenase,IDO)基因修饰的树突状细胞(dendritic cells,DCs)在体外对造血干细胞移植物中异基因T细胞增殖反应的抑制作用。〖HT5W〗方法〖HT5"SS〗: 用携带IDO基因的重组腺病毒转染BALB/c小鼠(受体)骨髓来源的DCs ,用RTPCR法检测DCs表面IDO的表达,用流式细胞术分析IDO基因修饰前后DC表型的变化,并把IDODC与C57BL/6小鼠(供体)脾脏来源  相似文献   

18.

Background:

Mounting evidence points to the efficacy of donor lymphocyte infusion (DLI) and immunisation with tumour-pulsed dendritic cells (DC) in generating graft vs leukaemia reactions after allogeneic bone marrow transplantation (BMT). We assessed the efficacy of DLI and DC in generating potent graft vs neuroblastoma tumour (GVT) reactions following allogeneic BMT.

Methods:

Mice bearing congenic (H2Ka) Neuro-2a tumours were grafted with allogeneic (H2Kb) T-cell-depleted bone marrow cells. Tumour-pulsed donor DC (DCNeuro2a) were inoculated (on day +7) in conjunction with donor (H2Kb) and haploidentical (H2Ka/b) lymphocytes.

Results:

Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice. Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DCNeuro2a and lymphocytes devoid of graft vs host (GVH) activity (H2Ka/b). In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT.

Conclsions:

The GVHD is not a prerequisite to induce GVT reactivity after allogeneic BMT, but is rather detrimental to induction of anti-tumour immunity by DC-mediated immunomodulation. Simultaneous inoculation of tumour-pulsed donor DC and DLI synergise in stimulation of potent GVT reactions to the extent of eradication of established NB tumours.  相似文献   

19.

Background:

Perspectives of immunotherapy to cancer mediated by bone marrow transplantation (BMT) in conjunction with dendritic cell (DC)-mediated immune sensitisation have yielded modest success so far. In this study, we assessed the impact of DC on graft vs tumour (GvT) reactions triggered by allogeneic BMT.

Methods:

H2Ka mice implanted with congenic subcutaneous Neuro-2a neuroblastoma (NB, H2Ka) tumours were irradiated and grafted with allogeneic H2Kb bone marrow cells (BMC) followed by immunisation with tumour-inexperienced or tumour-pulsed DC.

Results:

Immunisation with tumour-pulsed donor DC after allogeneic BMT suppressed tumour growth through induction of T cell-mediated NB cell lysis. Early post-transplant administration of DC was more effective than delayed immunisation, with similar efficacy of DC inoculated into the tumour and intravenously. In addition, tumour inexperienced DC were equally effective as tumour-pulsed DC in suppression of tumour growth. Immunisation of DC did not impact quantitative immune reconstitution, however, it enhanced T-cell maturation as evident from interferon-γ (IFN-γ) secretion, proliferation in response to mitogenic stimulation and tumour cell lysis in vitro. Dendritic cells potentiate GvT reactivity both through activation of T cells and specific sensitisation against tumour antigens. We found that during pulsing with tumour lysate DC also elaborate a factor that selectively inhibits lymphocyte proliferation, which is however abolished by humoral and DC-mediated lymphocyte activation.

Conclusion:

These data reveal complex involvement of antigen-presenting cells in GvT reactions, suggesting that the limited success in clinical application is not a result of limited efficacy but suboptimal implementation. Although DC can amplify soluble signals from NB lysates that inhibit lymphocyte proliferation, early administration of DC is a dominant factor in suppression of tumour growth.  相似文献   

20.
Connexin 43 (Cx43) induced apoptosis has been reported in solid tumors, but the effect of Cx43 expressed by bone marrow stromal cells (BMSC) in leukemia has not been fully investigated. Manipulating Cx43 expression could be a potential therapeutic strategy for leukemia. Here, we investigate the effect of Cx43 expressed by BMSCs (human Umbilical Cord Stem Cells over-expressed CX43, Cx43-hUCSC) on leukemia cells. When co-cultured with Cx43-hUCSC, leukemia cells show significant lower growth rate with increasing apoptosis activity, and more leukemia cells enter S phase. Functional assays of fluorescence recovery after photo bleaching (FRAP) showed improved gap junctional intercellular communication (GJIC) on leukemia cells when co-cultured with Cx43-hUCSC (p < 0.01). In a mouse minimal disease model, the mean survival time and mortality rate were significantly improved in mice transplanted with Cx43-hUCSC. Our results indicate that Cx43 expressed by BMSC induces apoptosis on leukemia cells. Small molecules or other pharmaceutical approaches for modulating Cx43 expression in BMSCs could be used for delaying relapse of leukemia.  相似文献   

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