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人类白细胞抗原-G(human leukocyte antigen G,HLA—G1属于非经典的HLAI类分子,是机体内重要的免疫耐受分子。HLA.G可以与表达在免疫细胞上的受体结合直接发挥免疫抑制功能,同时通过诱导产生调节性T细胞(regulatory Tcells,Treg)或“Trogocytosis”机制参与机体的免疫耐受,以协助肿瘤细胞实现免疫逃逸。近年来研究发现,HLA.G在多种恶性肿瘤中均存在异常表达并抑制宿主的抗肿瘤免疫反应。对HLA-G在肿瘤中的表达及可能的作用机制研究进展作一综述。 相似文献
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microRNAs(miRNAs)是一类转录后调控基因表达的内源性非编码微小RNA。愈来愈多的研究显示,miRNAs在肿瘤免疫应答中发挥重要调控作用。一方面,miRNAs通过转录后调控ICAM(intercellular adhesion molecule)、B7(CD80/86)和HLA—G(human leucocyte antigen—G)等肿瘤表面分子的表达,影响肿瘤的免疫原性;另一方面,miRNAs通过平衡肿瘤局部的细胞因子微环境或调控肿瘤免疫相关细胞的分化、发育及功能发挥,调节机体抗肿瘤免疫应答。为后续深入研究肿瘤与宿主的相互作用机制,以及发展更有效的肿瘤生物治疗手段,就目前miRNAs在肿瘤免疫中的调控作用的研究进展做一综述。 相似文献
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HLA-Ⅱ类分子与肿瘤 总被引:5,自引:0,他引:5
细胞免疫在机体抗肿瘤免疫占主导作用,其中HLA分子的作用更为关键。本文从HLA-Ⅱ类分子的角度,阐述它们在肿瘤的发生,发展和预后中的作用,及其在肿瘤免疫治疗领域中的应用前景。 相似文献
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一氧化氮的抗感染免疫作用及其机制 总被引:5,自引:0,他引:5
一氧化氮在机体抗感染免疫防御体系中的重要作用被发现之后,各国学者进行了大量的相关研究。这些研究证明:一氧化氮作为活化巨噬细胞的一种细胞毒效分子,在抑制和杀伤病毒,细菌,寄生虫等的免疫应答中起重要作用。一氧化氮抗感染的作用机制十分复杂,它通过调节Th1/Th2的平衡来促进机体的免疫应答,并可直接与含铁酶的Fe-S基团结合,破坏酶的活性,进而杀伤病原体及其宿主细胞。 相似文献
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人白细胞抗原G(HLA G)是一种在母婴耐受中起主要作用的非经典的HLA Ⅰ类分子 .其中HLA G3结构简单 ,仅具有α1结构域、穿膜区及胞浆区 ,其是否在细胞表面表达尚存在争议 .为了建立HLA G3稳定转染细胞株并确定其在细胞内的定位 ,采用RT PCR法从 9周人胎盘组织中获得了HLA G3的cDNA ,并构建到真核表达载体pcDNA3中 ,将所获得的真核表达质粒pcDNA G3转染至HLA Ⅰ (- )细胞株K5 6 2 ,经G4 18筛选后获得稳定转染的细胞株K5 6 2 G3.利用RT PCR、Western印迹检测方法证明在K5 6 2 G3细胞株中 ,HLA G3在mRNA水平和蛋白水平上均有表达 .进一步利用免疫荧光标记技术 ,证明HLA G3能够在转染细胞细胞膜上表达 .结果表明 ,稳定转染细胞株中HLA G3蛋白能够定位表达在细胞膜 相似文献
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周聪 《微生物学免疫学进展》1991,(1):3-11
自身抗独特型抗体(auto—ald)广泛存在于机体对多种抗原的免疫应答过程中,并通过与独特型(Id)相互作用,参与体液和/或细胞免疫应答的调节。auto-aId的调节作用包括:(1)通过抑制B细胞合成相应的Id抗体或激活Id特异性T细胞,后者作用于效应细胞,而反馈性抑制机体对起始抗原的免疫应答(向下调节);(2)内影像auto-aId模拟抗原,促进相应Id的表达(向上调节)。其调节作用在多数情况下对机体有利,如维持体内Id—抗—Id网络的稳定性,促进某些自身免疫病的恢复等。但在某些情况下则对机体有害,甚至导致某些受体自身免疫病的发生。 相似文献
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杀伤细胞免疫球蛋白样受体(KIR)主要表达在NK细胞和部分T细胞膜表面,通过识别细胞表达的MHC-Ⅰ类分子来调节NK细胞的活性,在病原体感染、自身免疫性疾病、妊娠、移植排斥、肿瘤等疾患中起重要作用,本文就近年来KIR及其配体HLA与相关疾病关系的研究作一综述。 相似文献
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HLA-G plays an important role in the induction of immune tolerance. Various attempts to produce good manufacturing practice levels of HLA-G as a therapeutic molecule have failed to date partly due to the complicated structure of full-length HLA-G1. Truncated HLA-G3 is simpler and easier to produce than HLA-G1 and contains the expected functional epitope in its only α1 monomorphic domain. In this study, we engineered the ER retrieval and retention signal on HLA-G3’s cytoplasmic tail by replacing its RKKSSD motif with RAASSD. We observed that mutated HLA-G3 was highly expressed on the cell surface of transduced K562 cells but did not inhibit cytotoxicity of natural killer cells. 相似文献
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Caumartin J Favier B Daouya M Guillard C Moreau P Carosella ED LeMaoult J 《The EMBO journal》2007,26(5):1423-1433
Trogocytosis is a fast uptake of membranes and associated molecules from one cell by another. Trogocytosis between natural killer (NK) cells and tumors is already described, but the functional relevance of NK-tumor targets material exchange is unclear. We investigated whether the immunosuppressive molecule HLA-G that is commonly expressed by tumors in vivo and known to block NK cytolytic function, could be transferred from tumor cells to NK cells, and if this transfer had functional consequences. We show that activated NK cells acquire HLA-G1 from tumor cells, and that upon this acquisition, NK cells stop proliferating, are no longer cytotoxic, and behave as suppressor cells. Such cells can inhibit other NK cells' cytotoxic function and protect NK-sensitive tumor cells from cytolysis. These data are the first demonstration that trogocytosis of HLA-G1 can be a major mechanism of immune escape that acts through effector cells made to act as suppressor cells locally, temporarily, but efficiently. The broader consequences of membrane sharing between immune and non-immune cells on the function of effectors and the outcome of immune responses are discussed. 相似文献
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A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape 总被引:32,自引:0,他引:32
Wiendl H Mitsdoerffer M Hofmeister V Wischhusen J Bornemann A Meyermann R Weiss EH Melms A Weller M 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(9):4772-4780
HLA-G is a nonclassical MHC molecule with highly limited tissue distribution that has been attributed chiefly immune regulatory functions. Glioblastoma is paradigmatic for the capability of human cancers to paralyze the immune system. To delineate the potential role of HLA-G in glioblastoma immunobiology, expression patterns and functional relevance of this MHC class Ib molecule were investigated in glioma cells and brain tissues. HLA-G mRNA expression was detected in six of 12 glioma cell lines in the absence of IFN-gamma and in 10 of 12 cell lines in the presence of IFN-gamma. HLA-G protein was detected in four of 12 cell lines in the absence of IFN-gamma and in eight of 12 cell lines in the presence of IFN-gamma. Immunohistochemical analysis of human brain tumors revealed expression of HLA-G in four of five tissue samples. Functional studies on the role of HLA-G in glioma cells were conducted with alloreactive PBMCs, NK cells, and T cell subpopulations. Expression of membrane-bound HLA-G1 and soluble HLA-G5 inhibited alloreactive and Ag-specific immune responses. Gene transfer of HLA-G1 or HLA-G5 into HLA-G-negative glioma cells (U87MG) rendered cells highly resistant to direct alloreactive lysis, inhibited the alloproliferative response, and prevented efficient priming of cytotoxic T cells. The inhibitory effects of HLA-G were directed against CD8 and CD4 T cells, but appeared to be NK cell independent. Interestingly, few HLA-G-positive cells within a population of HLA-G-negative tumor cells exerted significant immune inhibitory effects. We conclude that the aberrant expression of HLA-G may contribute to immune escape in human glioblastoma. 相似文献
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Modulation of HLA-G expression in human neural cells after neurotropic viral infections 总被引:1,自引:0,他引:1 下载免费PDF全文
Lafon M Prehaud C Megret F Lafage M Mouillot G Roa M Moreau P Rouas-Freiss N Carosella ED 《Journal of virology》2005,79(24):15226-15237
HLA-G is a nonclassical human major histocompatibility complex class I molecule. It may promote tolerance, leading to acceptance of the semiallogeneic fetus and tumor immune escape. We show here that two viruses-herpes simplex virus type 1 (HSV-1), a neuronotropic virus inducing acute infection and neuron latency; and rabies virus (RABV), a neuronotropic virus triggering acute neuron infection-upregulate the neuronal expression of several HLA-G isoforms, including HLA-G1 and HLA-G5, the two main biologically active isoforms. RABV induces mostly HLA-G1, and HSV-1 induces mostly HLA-G3 and HLA-G5. HLA-G expression is upregulated in infected cells and neighboring uninfected cells. Soluble mediators, such as beta interferon (IFN-beta) and IFN-gamma, upregulate HLA-G expression in uninfected cells. The membrane-bound HLA-G1 isoform was detected on the surface of cultured RABV-infected neurons but not on the surface of HSV-1-infected cells. Thus, neuronotropic viruses that escape the host immune response totally (RABV) or partially (HSV-1) regulate HLA-G expression on human neuronal cells differentially. HLA-G may therefore be involved in the escape of certain viruses from the immune response in the nervous system. 相似文献
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Le Discorde M Le Danff C Moreau P Rouas-Freiss N Carosella ED 《Biology of reproduction》2005,73(2):280-288
Expression of the nonclassical HLA class I antigen, HLA-G, is associated with immune tolerance in view of its role in maintaining the fetus in utero, allowing tumor escape, and favoring graft acceptance. Expressed on invasive trophoblast cells, HLA-G molecules bind inhibitory receptors on maternal T lymphocytes and NK cells, thereby blocking their cytolytic activities and protecting the fetus from maternal immune system attack. The HLA-G gene consists of 15 alleles, including a null allele, HLA-G*0105N. HLA-G*0105N presents a single base deletion, preventing translation of both membrane-bound (HLA-G1) and full-length soluble isoforms (HLA-G5) as well as of the spliced HLA-G4 isoform. The identification of healthy subjects homozygous for this HLA-G null allele suggests that the HLA-G*0105N allele may generate other HLA-G isoforms, such as membrane-bound HLA-G2 and -G3 and the soluble HLA-G6 and -G7 proteins, which may substitute for HLA-G1 and -G5, thus assuming the immune tolerogeneic function of HLA-G. To investigate this point, we cloned genomic HLA-G*0105N DNA and transfected it into an HLA-class I-positive human cell line. The results obtained indicated that HLA-G proteins were indeed present in HLA-G*0105N-transfected cells and were able to protect against NK cell lysis. These findings emphasize the role of the other HLA-G isoforms as immune tolerogeneic molecules that may also contribute to maternal tolerance of the semiallogenic fetus as well as tumor escape and other types of allogeneic tissue acceptance. 相似文献
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摘要:近年来,免疫治疗在晚期肾透明细胞癌的治疗中异军突起,使人们对于肾癌治疗有了全新的认识。肿瘤免疫治疗药物是通过抑制免疫检查点从而抑制肿瘤细胞免疫逃逸,使免疫细胞可以杀伤肿瘤细胞来发挥治疗作用。因此,了解肾透明细胞癌中免疫检查点相关免疫逃逸机制对于制定有效的治疗策略以及开发新的免疫治疗药物至关重要。本文对目前肾透明细胞癌中主要的免疫检查点(PD-1/PD-L1、CTLA-4、B7-H4、LAG-3、TIM-3和HLA-G)相关的免疫逃逸机制进行综述。 相似文献
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Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine 总被引:2,自引:0,他引:2
The non-classical HLA class Ⅰ antigen HLA-G is an immune modulator which inhibits the functions of T cells, NK cells, and the Dendritic cells (DC). As a result, HLA-G expression in malignant cells may provide them with a mechanism to escape the immune surveillance. In melanoma, HLA-G antigen expression has been found in 30% of surgically removed lesions but in less than 1% of established cell lines. One possible mechanism underlying the differential HLA-G expression in vivo and in vitro is that the HLA-G gene is epigenetically repressed in melanoma cells in vitro. To test this hypothesis, we treated the HLA-G negative melanoma cell line OCM-1A with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-AC) and analyzed whether HLA-G expression can be restored. Our data strongly suggest that HLA-G is silenced as a result of CpG hypermethylation within a 5' regulatory region encompassing 220 bp upstream of the start codon. After treatment, HLA-G mRNA expression was dramatically increased. Western blot and flow cytometry showed that HLA-G protein was induced. Interestingly, HLA-G cell surface expression on the 5-AC treated OCM-1A cells is much less than that on the HLA-G positive JEG-3 cells while a similar amount of total HLA-G was observed. Possible mechanisms for the difference were analyzed in the study such as cell cold-treatment, peptide loading and antigen processing machinery components (APM) as well as β2 microglobulin (β2-m) expression. Data revealed that the APM component calreticulin might be involved in the lower HLA-G surface expression on OCM-1A cells. Taken together, our results indicated that DNA methylation is an important epigenetic mechanism by which HLA-G antigen expression is modulated in melanoma cells in vitro. Furthermore, to the first time, we hypothesized that the deficiency of calreticulin might be involved in the low HLA-G surface expression on the 5-AC treated OCM-1A cells. 相似文献
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HLA-G inhibits rolling adhesion of activated human NK cells on porcine endothelial cells. 总被引:9,自引:0,他引:9
P Forte L Pazmany U B Matter-Reissmann G Stussi M K Schneider J D Seebach 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(10):6002-6008
Human NK cells adhere to and lyse porcine endothelial cells (pEC) and therefore may contribute to the cell-mediated rejection of vascularized pig-to-human xenografts. Since MHC class I molecules inhibit the cytotoxic activity of NK cells, the expression of HLA genes in pEC has been proposed as a potential solution to overcome NK cell-mediated xenogeneic cytotoxicity. HLA-G, a minimally polymorphic HLA class I molecule that can inhibit a wide range of NK cells, is an especially attractive candidate for this purpose. In this study we tested whether the expression of HLA-G on pEC inhibits the molecular mechanisms that lead to adhesion of human NK cells to pEC and subsequent xenogeneic NK cytotoxicity. To this end two immortalized pEC lines (2A2 and PED) were stably transfected with HLA-G1. Rolling adhesion of activated human NK cells to pEC monolayers and xenogeneic cytotoxicity against pEC mediated by polyclonal human NK lines as well as NK clones were inhibited by the expression of HLA-G. The adhesion was partially reversed by masking HLA-G on pEC with anti-HLA mAbs or by masking the HLA-G-specific inhibitory receptor ILT-2 on NK cells with the mAb HP-F1. The inhibition of NK cytotoxicity by HLA-G was only partially mediated by ILT-2, indicating a role for other unknown NK receptors. In conclusion, transgenic expression of HLA-G may be useful to prevent human NK cell responses to porcine xenografts, but is probably not sufficient on its own. Moreover, the blocking of rolling adhesion by HLA-G provides evidence for a novel biological function of HLA molecules. 相似文献