• 【重组人可溶性肿瘤坏死因子受体融合蛋白作为同种异体造血干细胞移植后类固醇难治性移植物抗宿主病的治疗方法。】 复制标题 收藏 收藏
    DOI:10.1002/ajh.20752 复制DOI
    作者列表:Busca A,Locatelli F,Marmont F,Ceretto C,Falda M
    BACKGROUND & AIMS: :Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.
    背景与目标: :Etanercept是一种重组人类可溶性肿瘤坏死因子(TNF-alpha)受体融合蛋白,可抑制TNF-alpha(一种在移植物抗宿主病(GVHD)发病机理中的主要介体)。本研究的目的是评估依那西普治疗21例激素抵抗性急性GVHD(aGVHD)(n = 13)和慢性GVHD(cGVHD)(n = 8)患者的安全性和有效性。每周两次皮下给予Etanercept 25 mg,持续4周,然后每周25 mg,持续4周。依那西普开始治疗时,有14例皮肤,13例胃肠,5例肝,5例肺,4例经口受累。 12名患者(57%)完成了12剂治疗。总体上,在21名患者中有11名患者(52%)对依那西普治疗有反应,包括6名患者(46%)患有aGVHD [n = 4完全缓解(CR),n = 2部分缓解(PR)]和5例(62 %)和cGVHD(n = 1 CR,n = 4 PR)。临床反应最常见于顽固性肠aGVHD患者,其中55%的患者为CR,9%的患者为PR。 CMV重新激活发生在48%的患者中,细菌感染发生在14%的患者中,而真菌感染发生在19%的患者中。自依那西普开始接受中位随访429天(71-1007天)后,有14名患者(67%)还活着。 7例患者死亡,3例感染,2例难治性aGVHD死亡,2例疾病进展。总之,我们的初步数据表明,依那西普耐受性好,在类固醇难治性aGVHD和cGVHD患者中可引起较高的应答率,尤其是在胃肠道受累的情况下。
  • 【T-T细胞相互作用是由粘附分子介导的。】 复制标题 收藏 收藏
    DOI:10.1002/eji.1830201015 复制DOI
    作者列表:Brod SA,Purvee M,Benjamin D,Hafler DA
    BACKGROUND & AIMS: :The mechanism by which T cells signal other T cells is not well defined. This was investigated by studying the ability of circulating T cells to induce the proliferation of autologous T cell clones. Peripheral blood T cells activated by cross-linking of the CD3/T cell receptor complex, which increased the expression of cell adhesion molecules LFA-1, LFA-3 and ICAM-1, induced the proliferation of autologous T cell clones. Irradiated antigen-activated peripheral blood T cells could also induce the proliferation of T cell clones which could not recognize that antigen. T-T cell activation required cell contact, was not major histocompatibility complex (MHC) restricted and was blocked by monoclonal antibodies directed against adhesion molecules CD2 and LFA-3 but was not blocked by antibody to class II MHC determinants. As CD2 is the natural ligand for LFA-3, increased expression of T cell surface adhesion molecules LFA-1, ICAM-1 and particularly LFA-3 during an inflammatory response may rapidly recruit T cells that are activated through the CD2 pathway. These results allow a simplified model to explain how relatively few antigen/MHC-specific T cells can recruit large numbers of non-antigen-specific T cells in the generation of an inflammatory response and postulates a novel role of the CD2 molecule in T cell immune function.
    背景与目标: :T细胞向其他T细胞发出信号的机制尚不明确。通过研究循环T细胞诱导自体T细胞克隆增殖的能力,对此进行了研究。通过CD3 / T细胞受体复合物交联而活化的外周血T细胞增加了细胞粘附分子LFA-1,LFA-3和ICAM-1的表达,诱导了自体T细胞克隆的增殖。辐射的抗原活化的外周血T细胞也可以诱导不能识别该抗原的T细胞克隆的增殖。 T-T细胞活化需要细胞接触,不受主要组织相容性复合物(MHC)的限制,并且被针对粘附分子CD2和LFA-3的单克隆抗体所阻断,但未被II类MHC决定簇的抗体所阻断。由于CD2是LFA-3的天然配体,因此在炎症反应期间T细胞表面粘附分子LFA-1,ICAM-1尤其是LFA-3的表达增加,可能会迅速募集通过CD2途径激活的T细胞。这些结果使简化的模型可以解释相对较少的抗原/ MHC特异性T细胞在炎症反应的产生中如何募集大量非抗原特异性T细胞,并推测CD2分子在T细胞免疫中的新作用功能。
  • 【在麻风病人中检测抗麻风分枝杆菌培养滤液蛋白10的抗体。】 复制标题 收藏 收藏
    DOI:10.1099/jmm.0.46587-0 复制DOI
    作者列表:Parkash O,Kumar A,Nigam A,Girdhar BK
    BACKGROUND & AIMS: :The prevalence of IgG antibodies against Mycobacterium leprae recombinant culture filtrate protein-10 (rCFP-10) was investigated in serum samples from 56 leprosy patients, 15 tuberculosis (TB) patients, 14 other skin-diseased patients and 20 healthy subjects. On classifying the patients into bacterial index (BI)-positive and BI-negative groups, the assay showed 83.3 % (15/18) sensitivity for detection of BI-positive leprosy patients. On the other hand, the sensitivity for detection of BI-negative patients was 18.4 % (7/38). None of the 15 TB patients and 14 other skin-diseased patients was positive; however, only one out of 20 healthy individuals was positive, indicating that antibody response to culture filtrate protein-10 (CFP-10) was highly specific (98.0 %; 48/49). Statistically, the performance of the CFP-10-based assay was found to be comparable (P>0.05) with that of an anti-phenolic glycolipid-I (PGL-I) antibody-detecting assay. Thus, M. leprae CFP-10 is potentially a specific antigen for measuring antibody response in BI-positive leprosy patients. Being a secreted antigen, CFP-10 may act as a marker for the viability of M. leprae inside the host, and hence its serological potential is worth exploring for application in monitoring the response of patients with BI-positive leprosy (a highly infectious form) during the course of chemotherapy. When comparing the bacteriological and serological results, an agreement of 82.1 % showed that seropositivity to M. leprae CFP-10 corresponded well with bacteriological criteria. Hence, CFP-10 seems to be a suitable antigen for classification of leprosy patients into BI-positive and BI-negative groups.
    背景与目标: :从56名麻风患者,15名结核病患者,14名其他皮肤病患者和20名健康受试者的血清样本中研究了抗麻风分枝杆菌重组培养物滤液蛋白-10(rCFP-10)IgG抗体的患病率。在将患者分为细菌指数(BI)阳性和BI阴性组后,该测定显示出83.3%(15/18)的灵敏度可检测BI阳性麻风病患者。另一方面,检测BI阴性患者的敏感性为18.4%(7/38)。 15例TB患者和14例其他皮肤病患者均无阳性。然而,在20个健康个体中只有1个是阳性,表明对培养滤液蛋白10(CFP-10)的抗体反应具有高度特异性(98.0%; 48/49)。从统计学上讲,发现基于CFP-10-的检测方法的性能可与抗酚糖脂I(PGL-1)抗体检测方法相媲美(P> 0.05)。因此,麻风分枝杆菌CFP-10潜在地是用于测量BI阳性麻风病患者的抗体应答的特异性抗原。 CFP-10是一种分泌性抗原,可作为宿主体内麻风分枝杆菌生存能力的标志物,因此其血清学潜力值得用于监测BI阳性麻风病患者(高度感染性)的反应中。 )在化疗过程中。当比较细菌学和血清学结果时,82.1%的一致性表明,对麻风分枝杆菌CFP-10的血清阳性与细菌学标准非常吻合。因此,CFP-10似乎是将麻风病人分为BI阳性和BI阴性组的合适抗原。
  • 【抗原特异性T细胞克隆在胶原疾病中的意义:用新型T细胞克隆性评估系统进行分析。】 复制标题 收藏 收藏
    DOI:10.2169/internalmedicine.36.242 复制DOI
    作者列表:Yamamoto K
    BACKGROUND & AIMS: The involvement of antigen-specific T cells in the pathogenesis of collagen diseases is still controversial. The final stages of collagen diseases are usually characterized by the dominance of inflammation. Therefore, antigen non-specific factors, such as inflammatory cytokines, probably play an important role in this process. On the other hand, the methods available to analyze the antigen-specific aspects of the immune response are still limited. Here we review our novel system of T cell clonality analysis based on the idea that activated antigen-specific T cells should form accumulating clones among the lymphocyte population. Using this method, dynamic changes of clonal accumulation of T cells could be evaluated during antigenic stimulation in vivo and in vitro. The significance of antigen-specific T cell clones in collagen diseases is discussed using data obtained from patients with rheumatoid arthritis and systemic lupus erythematosus.

    背景与目标: 抗原特异性T细胞是否参与胶原蛋白疾病的发病机制仍存在争议。胶原蛋白疾病的最后阶段通常以炎症占优势为特征。因此,抗原非特异性因子,例如炎性细胞因子,可能在此过程中起重要作用。另一方面,可用于分析免疫应答的抗原特异性方面的方法仍然有限。在这里,我们基于激活的抗原特异性T细胞应在淋巴细胞群体中形成累积克隆的想法,回顾了我们的T细胞克隆性分析的新系统。使用这种方法,可以在体内和体外抗原刺激过程中评估T细胞克隆积累的动态变化。利用类风湿性关节炎和系统性红斑狼疮患者获得的数据,讨论了抗原特异性T细胞克隆在胶原蛋白疾病中的重要性。

  • 【电离辐射以肺内不同的组织学模式介导细胞粘附分子的表达。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Hallahan DE,Virudachalam S
    BACKGROUND & AIMS: Inflammatory cell infiltration of the lung is a predominant histopathological change that occurs during radiation pneumonitis. Emigration of inflammatory cells from the circulation requires the interaction between cell adhesion molecules on the vascular endothelium and molecules on the surface of leukocytes. We studied the immunohistochemical pattern of expression of cell adhesion molecules in lungs from mice treated with thoracic irradiation. After X-irradiation, the endothelial leukocyte adhesion molecule 1 (ELAM-1; E-selectin) was primarily expressed in the pulmonary endothelium of larger vessels and minimally in the microvascular endothelium. Conversely, the intercellular adhesion molecule 1 (ICAM-1; CD54) was expressed in the pulmonary capillary endothelium and minimally in the endothelium of larger vessels. Radiation-mediated E-selectin expression was first observed at 6 h, whereas ICAM-1 expression initially increased at 24 h after irradiation. ICAM-1 and E-selectin expression persisted for several days. P-selectin is constitutively expressed in Weibel-Palade bodies in the endothelium, which moved to the vascular lumen within 30 min after irradiation. P-selectin was not detected in the pulmonary endothelium at 6 h after irradiation. The radiation dose required for increased cell adhesion molecule expression within the pulmonary vascular endothelium was 2 Gy, and expression increased in a dose-dependent manner. These data demonstrate that ICAM-1 and E-selectin expression is increased in the pulmonary endothelium following thoracic irradiation. The pattern of expression of E-selectin, P-selectin, and ICAM-1 is distinct from one another.

    背景与目标: 肺炎性细胞浸润是放射性肺炎期间发生的主要组织病理学变化。炎性细胞从循环系统的迁移需要血管内皮细胞粘附分子与白细胞表面分子之间的相互作用。我们研究了用胸腔照射治疗的小鼠肺中细胞粘附分子表达的免疫组织化学模式。 X射线照射后,内皮白细胞粘附分子1(ELAM-1; E-选择素)主要在较大血管的肺内皮中表达,而在微血管内皮中则最低表达。相反,细胞间粘附分子1(ICAM-1; CD54)在肺毛细血管内皮中表达,而在较大血管的内皮中表达最少。辐射介导的E-选择素表达首先在6 h观察到,而ICAM-1表达最初在辐射后24 h增加。 ICAM-1和E-选择素表达持续数天。 P-选择蛋白在内皮的Weibel-Palade体中组成性表达,在照射后30分钟内移至血管腔。照射后6 h在肺内皮中未检测到P-选择素。肺血管内皮细胞中细胞粘附分子表达增加所需的辐射剂量为2 Gy,并且表达以剂量依赖性方式增加。这些数据表明,胸腔照射后,肺内皮中的ICAM-1和E-选择蛋白表达增加。 E-选择素,P-选择素和ICAM-1的表达模式彼此不同。

  • 【MHC I类区域对巨细胞动脉炎遗传易感性的贡献。】 复制标题 收藏 收藏
    DOI:10.1093/rheumatology/kel324 复制DOI
    作者列表:Gonzalez-Gay MA,Rueda B,Vilchez JR,Lopez-Nevot MA,Robledo G,Ruiz MP,Fernández O,Garcia-Porrua C,Gonzalez-Escribano MF,Martín J
    BACKGROUND & AIMS: OBJECTIVE:The aim of this study was to assess the potential contribution of HLA-class I MICA and HLA-B gene polymorphisms towards the pathogenesis of giant cell arteritis (GCA). METHODS:Ninety-eight biopsy-proven GCA patients and 225 ethnically matched controls from Lugo, Northwest Spain, were genotyped for the MICA-TM microsatellite polymorphism using a polymerase chain reaction (PCR)-based method. Genotyping of HLA-B was performed using PCR and detection with a reverse sequence-specific oligonucleotide (SSO) probes system. RESULTS:A significant difference in the distribution of the alleles of MICA between patient and control groups (P = 0.005) was found. This was due to an increased frequency of the MICA A5 allele in GCA patients compared with controls (26 vs 13.6%; P = 0.0001; P(C) = 0.0005; OR 2.2, 95% CI 1.4-3.4). In addition, the HLA-B*15 allele showed a higher frequency in GCA patients compared with controls (P = 0.004; P(C) = 0.04; OR 2.7, 95% CI 1.3-5.7). Interestingly, the association observed with the MICA A5 allele seems to be independent of linkage disequilibrium with HLA-B, as well as independent of that previously described with HLA-DRB1*04. Remarkably, simultaneous presence of MICA A5 and HLA-B*15 or HLA-DRB1*04 genetic markers leads to an increase in the OR obtained for each individual genetic marker (MICA A5 + B*15 OR 3.2; MICA A5 + DRB1*04 OR 5.8). CONCLUSIONS:Our results provide the first evidence that the MICA and HLA-B genes are independently associated with the genetic susceptibility to GCA, and suggest that several genes within the MHC might have independent effects in the susceptibility to this systemic vasculitis.
    背景与目标: 目的:本研究旨在评估HLA I类MICA和HLA-B基因多态性对巨细胞性动脉炎(GCA)发病的潜在作用。
    方法:采用聚合酶链反应(PCR)方法,对来自西班牙西北部卢戈市的98例活检证实的GCA患者和225名种族匹配的对照进行了MICA-TM微卫星多态性的基因分型。使用PCR进行HLA-B的基因分型,并使用反向序列特异性寡核苷酸(SSO)探针系统进行检测。
    结果:在患者和对照组之间,MICA等位基因的分布存在显着差异(P = 0.005)。这是由于与对照相比,GCA患者中MICA A5等位基因的频率增加(26比13.6%; P = 0.0001; P(C)= 0.0005; OR 2.2,95%CI 1.4-3.4)。此外,与对照相比,GCA患者的HLA-B * 15等位基因频率更高(P = 0.004; P(C)= 0.04; OR 2.7,95%CI 1.3-5.7)。有趣的是,与MICA A5等位基因所观察到的关联似乎独立于与HLA-B的连锁不平衡,也独立于先前对HLA-DRB1 * 04的描述。值得注意的是,同时存在MICA A5和HLA-B * 15或HLA-DRB1 * 04遗传标记会导致每个单独的遗传标记获得的OR升高(MICA A5 B * 15或3.2; MICA A5 DRB1 * 04 OR 5.8 )。
    结论:我们的结果提供了第一个证据,表明MICA和HLA-B基因与对GCA的遗传易感性独立相关,并表明MHC中的几个基因可能对该系统性血管炎的易感性具有独立影响。
  • 【通过过继转移CD4抗肿瘤T细胞杀死原位大鼠腺癌13762需要细胞表面MHC II类分子的肿瘤表达。】 复制标题 收藏 收藏
    DOI:10.1006/cimm.1997.1122 复制DOI
    作者列表:Frey AB,Cestari S
    BACKGROUND & AIMS: CD4+ anti-tumor T cells reactive with rat adenocarcinoma 13762 kill tumor in vitro and cause regression of tumor in vivo. The role of various host immune cells in CD4+ T-cell-mediated tumor elimination in vivo was investigated by adoptive transfer of anti-tumor T cell clones to recipients that were selectively depleted of individual immune cell types. By these means, macrophages and NK cells were found to be required for tumor killing. Depletion of host CD4+ T cells, CD8+ T cells, or neutrophils was without effect on tumor elimination by anti-tumor T cells. An essential role for antigen receptor-negative NK cells is likely dependent upon secretion of IFN-gamma from NK cells since treatment of tumor recipients with anti-IFN-gamma antibody prior to adoptive transfer and tumor challenge abrogated T cell killing, resulting in progressive tumor growth. Viability of adenocarcinoma 13762 or anti-tumor T cells was unaffected by treatment with either IFN-gamma or anti-IFN-gamma antibody in vitro, but cell surface MHC class II expression was induced in tumor cells by exposure to IFN-gamma. In addition, tumor cells were isolated from tumor-bearing animals by absorption using anti-MHC class II antibody, demonstrating that 13762 tumor expresses cell surface MHC class II antigens in situ. However, if hosts were depleted of NK cells before tumor challenge, MHC class II+ tumor was not recovered. Collectively these results suggest that adenocarcinoma 13762 is eliminated by MHC class II-restricted CD4+ T cells by direct tumor killing.

    背景与目标: 与大鼠腺癌13762反应的CD4抗肿瘤T细胞在体外杀死肿瘤并在体内引起肿瘤消退。通过将抗肿瘤T细胞克隆过继转移到选择性清除了个体免疫细胞类型的受体上,研究了各种宿主免疫细胞在体内CD4 T细胞介导的肿瘤消除中的作用。通过这些手段,发现杀死肿瘤需要巨噬细胞和NK细胞。宿主CD4 T细胞,CD8 T细胞或嗜中性白细胞的耗竭对抗肿瘤T细胞对肿瘤的消除没有影响。抗原受体阴性NK细胞的重要作用可能取决于NK细胞分泌IFN-γ,因为在过继转移和肿瘤攻击之前用抗IFN-γ抗体治疗肿瘤受体可以消除T细胞杀伤,从而导致进行性肿瘤生长。体外用IFN-γ或抗IFN-γ抗体治疗不会影响腺癌13762或抗肿瘤T细胞的存活率,但通过暴露于IFN-γ诱导了肿瘤细胞的细胞表面MHC II类表达。另外,通过使用抗MHC II类抗体的吸收从荷瘤动物中分离出肿瘤细胞,表明13762肿瘤原位表达细胞表面MHC II类抗原。但是,如果宿主在肿瘤攻击前已耗尽NK细胞,则无法恢复MHC II类肿瘤。这些结果共同表明,通过直接杀死肿瘤,MHC II类限制性CD4 T细胞可消除13762腺癌。

  • 【垂体激素调节胸腺细胞和胸腺上皮细胞之间的细胞间相互作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0165-5728(97)00031-3 复制DOI
    作者列表:de Mello-Coelho V,Villa-Verde DM,Dardenne M,Savino W
    BACKGROUND & AIMS: The thymic microenvironment plays a key role in the intrathymic T-cell differentiation. It is composed of a tridimensional network of epithelial cells whose physiology is controlled by extrinsic circuits such as neuroendocrine axes. Herein we show that the expression of extracellular matrix ligands and receptor by cultured thymic epithelial cells is upregulated by prolactin (PRL) and growth hormone (GH), the latter apparently occurring via insulin-like growth factor I (IGF-I). Thymocyte release from the lymphoepithelial complexes, thymic nurse cells, as well as the reconstitution of these complexes are enhanced by PRL, GH or IGF-I. Treatment of a mouse thymic epithelial cell line with these hormones induced an increase in thymocyte adhesion, an effect significantly prevented in the presence of antibodies to fibronectin, laminin or respective receptors VLA-5 and VLA-6. Our data suggest that the in vitro changes in thymocyte/thymic epithelial cell interactions induced by pituitary hormones are partially mediated by the enhancement of extracellular matrix ligands and receptors.

    背景与目标: 胸腺微环境在胸腺内T细胞分化中起关键作用。它由上皮细胞的三维网络组成,其上皮细胞的生理受到外在回路(如神经内分泌轴)的控制。本文中我们显示,培养的胸腺上皮细胞的细胞外基质配体和受体的表达被催乳素(PRL)和生长激素(GH)上调,后者显然是通过胰岛素样生长因子I(IGF-1)发生的。 PRL,GH或IGF-I增强了从淋巴上皮复合物,胸腺护士细胞释放胸腺细胞以及这些复合物的重构。用这些激素处理小鼠胸腺上皮细胞系可诱导胸腺细胞粘附增加,在存在针对纤连蛋白,层粘连蛋白或相应受体VLA-5和VLA-6的抗体的情况下,该作用被显着阻止。我们的数据表明,垂体激素诱导的胸腺细胞/胸腺上皮细胞相互作用的体外变化部分由细胞外基质配体和受体的增强介导。

  • 【缺氧条件下的肿瘤基质细胞相互作用通过肝细胞生长因子/ c-Met途径增加了胰腺癌细胞的侵袭性。】 复制标题 收藏 收藏
    DOI:10.1002/ijc.22178 复制DOI
    作者列表:Ide T,Kitajima Y,Miyoshi A,Ohtsuka T,Mitsuno M,Ohtaka K,Koga Y,Miyazaki K
    BACKGROUND & AIMS: :The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1alpha expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1alpha expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1alpha expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer.
    背景与目标: :据报道肿瘤中的低氧环境在胰腺癌的进展中起重要作用。基质细胞与癌细胞之间的相互作用也有助于胰腺癌的恶性行为。在本研究中,我们调查了低氧刺激是否影响基质和胰腺癌细胞。我们的研究结果表明,缺氧显着提高了胰腺癌(PK8)和成纤维细胞(MRC5)中HIF-1alpha的表达。低氧刺激加速了PK8细胞的侵袭活性,因此,当用由低氧MRC5细胞制备的条件培养基(低氧条件培养基)培养低氧PK8细胞时,侵袭性进一步加快。在缺氧条件下,PK8细胞中的MMP-2,MMP-7,MT1-MMP和c-Met表达增加。缺氧刺激还增加了MRC5细胞的肝细胞生长因子(HGF)分泌,这导致PK8细胞中c-Met磷酸化的升高。相反,通过从低氧条件培养基中除去HGF,可以降低PK8细胞的癌浸润,MMP活性和c-Met磷酸化升高。在免疫组织化学研究中,在周围的基质细胞和胰腺癌细胞中均观察到了HIF-1alpha的表达,因此表明在癌细胞和基质细胞中均存在缺氧。此外,发现基质HGF表达不仅与癌细胞中的基质HIF-1α表达而且与c-Met表达显着相关。这些结果表明基质以及癌细胞内的低氧环境激活了HGF / c-Met系统,从而促进了胰腺癌的侵袭性侵袭性特征。
  • 10 B-cell memory: are subsets necessary? 复制标题 收藏 收藏

    【B细胞记忆:是否需要子集?】 复制标题 收藏 收藏
    DOI:10.1038/nri1938 复制DOI
    作者列表:Tarlinton D
    BACKGROUND & AIMS: :B-cell memory is provided by populations of quiescent memory B cells and long-lived plasma cells. Whereas it is clear that both of these cell populations arise from germinal centres, the signals and circumstances that trigger germinal-centre B cells to enter and then persist in memory compartments are poorly defined. Here, I propose that germinal centres produce memory B cells and plasma cells throughout the immune response and that memory B cells arise by the emigration of B cells that are chosen at random from the pool available in the germinal centre. The ability of such emigrants to survive as memory B cells depends on their germinal-centre 'history', with the persistence of high-affinity B-cell variants being favoured.
    背景与目标: :B细胞记忆由静态记忆B细胞和长寿浆细胞群体提供。显然,这两个细胞群均起源于生发中心,但触发生发中心B细胞进入并随后在记忆区室中存留的信号和环境的定义不明确。在这里,我建议生发中心在整个免疫反应过程中都会产生记忆B细胞和浆细胞,而记忆B细胞则是通过迁移B细胞而产生的,这些B细胞是从生发中心可用的池中随机选择的。这些移出者作为记忆B细胞存活的能力取决于它们的生发中心“历史”,而高亲和力B细胞变体的持久性受到青睐。
  • 【T细胞记忆和接种疫苗的保护性免疫力更好吗?】 复制标题 收藏 收藏
    DOI:10.1016/j.it.2006.09.004 复制DOI
    作者列表:Zanetti M,Franchini G
    BACKGROUND & AIMS: :Protection against intracellular pathogens or tumor antigens requires T-cell mediated responses. Recently, it has become apparent that protection against disease correlates with T cells of the central memory type in many instances. Here, we analyze current data to distill a set of rules for the induction and maintenance of central memory T-cell responses. Recent studies show that T-cell help and the lack of overt inflammation at the time of priming are prerequisite for the induction, maintenance and expansion of memory T cells. Central to our hypothesis is that, in addition to these factors, successful vaccination in the immunologically inexperienced individual should be based on low antigen dose, to decelerate replicative senescence in responding cells and favor lineage differentiation of central memory T cells. In the immunologically experienced individual, it will be necessary, in addition, to abate the antigen load in plasma before vaccination. These guiding principles might help to raise improved protective T-cell responses by vaccination in humans.
    背景与目标: :对细胞内病原体或肿瘤抗原的保护需要T细胞介导的反应。最近,很明显,在许多情况下,针对疾病的保护与中央记忆型T细胞相关。在这里,我们分析当前数据以提炼出一套诱导和维持中央记忆T细胞反应的规则。最近的研究表明,在引发时,T细胞的帮助和缺乏明显的炎症是诱导,维持和扩展记忆T细胞的先决条件。我们假说的中心在于,除这些因素外,对免疫缺乏经验的个体进行的成功疫苗接种应基于低抗原剂量,以减慢应答细胞中的复制衰老并有利于中央记忆T细胞的谱系分化。对于具有免疫学经验的个人,此外,有必要在接种疫苗之前减轻血浆中的抗原负荷。这些指导原则可能有助于通过接种疫苗来提高保护性T细胞反应。
  • 【在使用电纺聚合物支架的三维培养系统中,鼠胚胎干细胞的成脂作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.biomaterials.2006.08.052 复制DOI
    作者列表:Kang X,Xie Y,Powell HM,James Lee L,Belury MA,Lannutti JJ,Kniss DA
    BACKGROUND & AIMS: :A mechanistic understanding of adipose tissue differentiation is critical for the treatment and prevention of obesity and type 2 diabetes. Conventional in vitro models of adipogenesis are preadipocytes or freshly isolated adipocytes grown in two-dimensional (2D) cultures. Optimal results using in vitro tissue culture models can be expected only when adipocyte models closely resemble adipose tissue in vivo. Thus the design of an in vitro three-dimensional (3D) model which faithfully mimics the in vivo environment is needed to effectively study adipogenesis. Pluripotent embryonic stem (ES) cells are a self-renewing cell type that can readily be differentiated into adipocytes. In this study, a 3D culture system was developed to mimic the geometry of adipose tissue in vivo. Murine ES cells were seeded into electrospun polycaprolactone scaffolds and differentiated into adipocytes in situ by hormone induction as demonstrated using a battery of gene and protein expression markers along with the accumulation of neutral lipid droplets. Insulin-responsive Akt phosphorylation, and beta-adrenergic stimulation of cyclic AMP synthesis were demonstrated in ES cell-derived adipocytes. Morphologically, ES cell-derived adipocytes resembled native fat cells by scanning electron and phase contrast microscopy. This tissue engineered ES cell-matrix model has potential uses in drug screening and other therapeutic developments.
    背景与目标: :对脂肪组织分化的机械理解对于肥胖症和2型糖尿病的治疗和预防至关重要。脂肪形成的常规体外模型是在二维(2D)培养物中生长的前脂肪细胞或新鲜分离的脂肪细胞。仅当脂肪细胞模型与体内脂肪组织非常相似时,才能期望使用体外组织培养模型获得最佳结果。因此,需要忠实地模拟体内环境的体外三维(3D)模型的设计才能有效地研究脂肪形成。多能胚胎干(ES)细胞是一种自我更新的细胞类型,可以很容易地分化为脂肪细胞。在这项研究中,开发了一种3D培养系统来模拟体内脂肪组织的几何形状。将鼠ES细胞接种到电纺聚己内酯支架中,并通过激素诱导原位分化为脂肪细胞,如使用一系列基因和蛋白质表达标记以及中性脂质滴的积累所证明的。在ES细胞衍生的脂肪细胞中证实了胰岛素反应性Akt磷酸化和β-肾上腺素能刺激环状AMP的合成。形态上,通过扫描电子和相差显微镜,ES细胞来源的脂肪细胞类似于天然脂肪细胞。这种组织工程化的ES细胞基质模型在药物筛选和其他治疗发展中具有潜在用途。
  • 【B细胞慢性淋巴细胞性白血病患者T细胞中的信号分子和细胞因子产生:氟达拉滨和alemtuzumab治疗的长期效果。】 复制标题 收藏 收藏
    DOI:10.1080/10428190600565503 复制DOI
    作者列表:Kiaii S,Choudhury A,Mozaffari F,Rezvany R,Lundin J,Mellstedt H,Osterborg A
    BACKGROUND & AIMS: :Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.
    背景与目标: :氟达拉滨和阿仑单抗通常用于治疗B细胞慢性淋巴细胞性白血病(B-CLL)。本研究旨在比较氟达拉滨或alemtuzumab治疗后长期未维持的缓解/高原期的B-CLL患者的信号分子表达和T细胞的细胞因子产生与惰性/未经治疗的B-CLL患者和健康供体的长期比较。通过流式细胞术检测TCR-CD3zeta链,p56lck,p59fyn,ZAP-70,PI3-激酶和干扰素(IFN)-γ/白介素(IL)-4在CD4和CD8 T细胞中产生的频率和强度。通过用纯化的蛋白质衍生物(PPD)和植物血凝素(PHA)刺激来评估T细胞功能。尽管数量减少,但患者T细胞中IFN-γ/ IL-4的表达明显高于健康供体。与健康供体相比,已治疗患者中大多数信号分子的强度相对未受影响,但低于未治疗的惰性患者。但是,表达每种信号分子的T细胞总数在患者中减少了,在氟达拉滨和阿仑单抗治疗的患者之间没有差异。在治疗的患者中,对PHA而非TPD的T细胞反应降低了。结果表明,尽管在用氟达拉滨和阿仑单抗治疗后,长期而言,尽管信号分子发生了某些变化并且T细胞数量有所减少,但总体T细胞功能仍可以得到较好的保留。
  • 【阴道和子宫颈的透明细胞腺癌。荷兰中部注册表的更新显示双胞胎年龄发病高峰。】 复制标题 收藏 收藏
    DOI:10.1002/(sici)1097-0142(19970601)79:11<2229::aid-c 复制DOI
    作者列表:Hanselaar A,van Loosbroek M,Schuurbiers O,Helmerhorst T,Bulten J,Bernhelm J
    BACKGROUND & AIMS: BACKGROUND:The objective of this study was to update the registry of women in the Netherlands with clear cell adenocarcinoma (CCAC) of the cervix or vagina with or without intrauterine exposure to diethylstilbestrol (DES). METHODS:From a nationwide search in PALGA, the automated pathology registry in the Netherlands, data were gathered on women with CCAC born after 1947. Information obtained from the clinical files of the patients included reported exposure to DES, patterns of complaints previous to diagnosis, the current status of the patients, and the results of cytopathologic examinations previous to histopathologic diagnosis. After review of the histopathologic slides, the specific pathologic characteristics of CCAC were determined. The age distribution of women born after 1947 was compared with that of women born before 1947. RESULTS:Information about possible exposure to DES during pregnancy was available for 73 of 88 women with CCAC born after 1947. Exposure to DES was reported for 47 (64%) of these women. The DES medication was most often reported as having started before the 18th week of pregnancy. Cytopathologic examination was informative in 81% of the cases of CCAC of the cervix, but only in 41% of the cases of CCAC of the vagina. Most patients had Stage I or II tumors at diagnosis. Tumor Stage III and IV and a high grade of nuclear atypia were related to unfavorable outcome. The age distribution of all patients with CCAC showed two distinct peaks; one at young age, (a mean age of 26 years), and one at older age (a mean age of 71 years). This bimodal age distribution still applied when the cases in which DES exposure was reported had been excluded. CONCLUSIONS:Despite the fact that DES has not been prescribed to pregnant women in the Netherlands in the last 20 years, CCAC is still relevant in our times. It is important to stay alert and periodically to update and evaluate the data of this registry, including data on women born outside the DES exposure period. The bimodal age distribution in this study of women without intrauterine exposure to DES suggests a carcinogenesis-promoting role of menarche and menopause and/ or the existence of a subpopulation with genetic risk factors or exogenous risk factors other than exposure to DES. Postmenopausal observation of women exposed to DES must be encouraged for clinical reasons and may help facilitate differentiation between these two hypotheses. If these risk factors of CCAC were better documented and their interrelationships better defined, CCAC could become an important model of multistep carcinogenesis in tissues sensitive to sex hormones.
    背景与目标: 摘要背景:这项研究的目的是更新荷兰妇女宫颈或阴道透明细胞腺癌(CCAC)宫腔内或不暴露于己烯雌酚(DES)的女性登记资料。
    方法:通过在荷兰的自动病理注册机构PALGA进行的全国性搜索,收集了1947年以后出生的CCAC妇女的数据。从患者的临床档案中获得的信息包括报告的DES暴露,诊断前的投诉模式,患者的当前状况以及组织病理学诊断之前的细胞病理学检查结果。在回顾了组织病理学切片之后,确定了CCAC的具体病理学特征。比较了1947年以后出生的妇女和1947年之前出生的妇女的年龄分布。
    结果:1947年后出生的88例CCAC妇女中有73例可获得有关怀孕期间可能接触DES的信息。据报道,这些女性中有47例(64%)接触DES。据报道,DES药物是在怀孕第18周之前开始服用的。在81%的子宫颈CCAC病例中,细胞病理学检查是有益的,但在阴道的CCAC病例中仅41%。大多数患者在诊断时患有I期或II期肿瘤。肿瘤的第三和第四阶段以及高度的核非典型性与不良预后有关。所有CCAC患者的年龄分布均出现两个明显的高峰。一位年龄较小(平均年龄26岁),一位年龄较大(平均年龄71岁)。当排除了报道有DES暴露的病例时,这种双峰年龄分布仍然适用。
    结论:尽管在过去的20年中荷兰没有为孕妇开具DES,但CCAC在我们这个时代仍然具有现实意义。重要的是要保持警惕,并定期更新和评估该注册表的数据,包括有关DES暴露期以外出生的妇女的数据。在这项研究中,没有宫内暴露于DES的妇女的双峰年龄分布表明,月经初潮和更年期的致癌作用和/或除了暴露于DES之外,还存在具有遗传危险因素或外源危险因素的亚群。出于临床原因,必须鼓励对接受DES的妇女进行绝经后观察,这可能有助于促进这两种假说之间的区分。如果更好地记录CCAC的这些危险因素并更好地定义它们之间的相互关系,CCAC可能会成为对性激素敏感的组织中多步骤癌变的重要模型。
  • 【CD5(Ly-1)阴性的常规脾脏B细胞对CBA和BW小鼠的菠萝蛋白酶空斑形成细胞反应做出了重要贡献。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Andrew EM,Annis W,Kahan M,Maini RN
    BACKGROUND & AIMS: :CD5 (Ly-1) B cells are a minor subpopulation in mouse spleen and are thought to be responsible for the production of natural autoantibodies to bromelain-treated autologous erythrocytes (Br-RBC). Here it is shown that substantial numbers of conventional, CD5-negative, splenic B cells also secrete these antibodies in CBA and (NZB x NZW)F1 mice, whereas in NZB and BALB/c mice they are all produced by the CD5 B-cell population. However, stimulation with bacterial lipopolysaccharide in vivo preferentially activates the CD5 B-cell group to anti-Br-RBC antibody secretion.
    背景与目标: :CD5(Ly-1)B细胞是小鼠脾脏中的次要亚群,被认为负责产生与菠萝蛋白酶处理的自体红细胞(Br-RBC)的天然自身抗体。在此表明,大量常规的CD5阴性脾脏B细胞也在CBA和(NZB x NZW)F1小鼠中分泌这些抗体,而在NZB和BALB / c小鼠中,它们都是由CD5 B细胞产生的人口。然而,在体内用细菌脂多糖刺激可优先激活CD5 B细胞基团以分泌抗Br-RBC抗体。

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