Yun Chen

Nanjing Medical University, Nanjing, Jiangsu Sheng, China

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Publications (18)60.5 Total impact

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    ABSTRACT: Epstein-Barr Virus-encoded latent membrane protein 2A (LMP2A) promotes the epithelial-mesenchymal transition (EMT) of nasopharyngeal carcinoma (NPC), thereby increasing tumor invasion. Recently, the dysregulation of metastatic tumor antigen 1 (MTA1) was found to enhance tumor metastasis in a variety of cancers. A molecular connection between these two proteins has been proposed but not firmly established. In this study, we reported the overexpression of MTA1 in 29/60 (48.3%) NPC patients and the overexpression of MTA1 significantly correlated with tumor metastasis. The overexpression of MTA1 promoted EMT via the Wnt1 pathway and β-catenin activation. We demonstrated that LMP2A reinforces the expression of MTA1 via the mechanistic target of rapamycin (mTOR) pathway to promote EMT in NPC. Furthermore, by knocking-down of 4EBP1 in combination with the new mTOR inhibitor INK-128 treatment, we discovered that LMP2A expression activates the 4EBP1-eIF4E axis and increases the expression of MTA1 at the translational level, partial independent of c-myc. These findings provided novel insights into the correlation between the LMP2A and MTA1 proteins and reveal a novel function of the 4EBP1-eIF4E axis in EMT of nasopharyngeal carcinoma.
    Journal of virology. 08/2014;
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    ABSTRACT: Attenuated Listeria monocytogenes (LM) is a promising candidate vector for the delivery of cancer vaccines. After phagocytosis by antigen-presenting cells, this bacterium stimulates the major histocompatibility complex (MHC)-I and MHC-II pathways and induces the proliferation of antigen-specific T lymphocytes. A new strategy involving genetic modification of the replication-deficient LM strain ΔdalΔdat (Lmdd) to express and secrete human CD24 protein has been developed. CD24 is a hepatic cancer stem cell biomarker that is closely associated with apoptosis, metastasis and recurrence of hepatocellular carcinoma (HCC). After intravenous administration in mice, Lmdd-CD24 was distributed primarily in the spleen and liver and did not cause severe organ injury. Lmdd-CD24 effectively increased the number of interferon (IFN)-γ-producing CD8(+) T cells and IFN-γ secretion. Lmdd-CD24 also enhanced the number of IL-4- and IL-10-producing T helper 2 cells. The efficacy of the Lmdd-CD24 vaccine was further investigated against Hepa1-6-CD24 tumors, which were inguinally inoculated into mice. Lmdd-CD24 significantly reduced the tumor size in mice and increased their survival. Notably, a reduction of T regulatory cell (Treg) numbers and an enhancement of specific CD8(+) T-cell activity were observed in the tumor-infiltrating lymphocytes (TILs). These results suggest a potential application of the Lmdd-CD24 vaccine against HCC.Cellular & Molecular Immunology advance online publication, 3 February 2014; doi:10.1038/cmi.2013.64.
    Cellular & molecular immunology 02/2014; · 3.42 Impact Factor
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    ABSTRACT: Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus. The mechanisms by which HHV-6 establishes latency and immunosuppression in its host are not well understood. Here we characterized HHV-6-specific T cells in peripheral blood mononuclear cells (PBMCs) from HHV-6-infected donors. Our results showed that HHV-6 infection could induce both CD4(+) and CD8(+) HHV-6-specific regulatory T (Treg) cells. These HHV-6-specific Treg cells had potent suppressive activity and expressed high levels of Treg-associated molecules CD25, FoxP3 and GITR. Both CD4(+) and CD8(+) Treg cells secreted IFN-γ, IL-10, but little or no IL-2, IL-4 or TGF-β. Furthermore, HHV-6-specifc Treg cells could not only suppress naïve and HHV-6-specific CD4(+) effector T cell immune responses, but also impair dendritic cell (DC) maturation and functions. In addition, the suppressive effects mediated by HHV-6-specific Treg cells were mainly through a cell-to-cell contact dependent mechanism, but not through the identified cytokines. These results suggest that HHV-6 may utilize the induction of Treg cells as a strategy to escape anti-virus immune responses and maintain the latency and immunosuppression in infected hosts.
    Journal of Virology 11/2013; · 5.08 Impact Factor
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    ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting cellular tumor vaccines contribute to the induction of potent antitumor immune responses in murine models and patients suffering from cancers. Hepatocellular carcinoma (HCC) is one of the most frequent and malignant cancers in China. We describe, for the first time, a GM-CSF releasing vaccine strategy that represents a step toward combating this type of cancer. In this study, a bystander cell-based GM-CSF secreting vaccine against murine HCC, Hepa1-6/B78H1-GM-CSF, was co-administered with a low dose of cyclophosphamide (CY). After challenging with tumor and vaccination, immunological assays demonstrated that the cellular antitumor immune responses were efficiently activated and that tumor development was significantly retarded, which was dependent on synergy with CY. The promising outcome of the anti-HCC vaccine in the murine model demonstrates the feasibility of a future clinical application for this treatment in HCC patients.Cellular & Molecular Immunology advance online publication, 20 May 2013; doi:10.1038/cmi.2013.20.
    Cellular & molecular immunology 05/2013; · 3.42 Impact Factor
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    ABSTRACT: The role of transforming growth factor-beta (TGF-β) signaling in hepatocarcinogenesis remains controversial. We aimed to reveal TGF-β signaling status in human and murine tissues of hepatocellular carcinoma (HCC) and the mechanisms that mediate TGF-β's role in regulating HCC malignancy. Here, TGF-β pathway component expression and activation in human and murine HCC tissues were measured with quantitative RT-PCR and Western blotting assays. The role of TGF-β receptor and Smad signaling in the growth and survival of several HCC cell lines was determined with several in vitro and in vivo approaches. We found that TGF-β receptor II (TβRII) expression was downregulated in two different HCC patient cohorts. Consistently, Smad3 phosphorylation was also downregulated in HCC tissues in comparison to that in adjacent normal tissues. Interestingly, many HCC cell lines were sensitive to TGF-β and growth-inhibited by exogenous TGF-β. However, stable knockdown of TβRII inhibited cell growth on plastic and in soft agar, and induced apoptosis resulting in suppressed subcutaneous tumor growth and metastatic potential in vivo. Furthermore, knockdown of Smad4 also led to a significant inhibition of growth on plastic and in soft agar with concomitant increase of apoptosis, PTEN expression, and reduced nuclear accumulation of linker region-phosphorylated Smad3. Taken together, TGF-β signaling pathway plays a dichotomous role in hepatocellular carcinogenesis. It appears to suppress HCC development, but is retained for HCC cell survival and malignancy. Furthermore, Smad4 can mediate both growth inhibitory activity induced by exogenous TGF-β and the survival activity induced by autocrine TGF-β revealing a delicate selection of the two opposing activities of TGF-β during HCC evolution.
    PLoS ONE 01/2013; 8(5):e63436. · 3.53 Impact Factor
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    ABSTRACT: The etiology of glioma remains unclear so far. Human herpesvirus 6 (HHV-6) might be associated with glioma, but there is no direct evidence to support this. High percentages of HHV-6 DNA and protein were detected in tissue from gliomas, compared with normal brain tissue. In addition, a strain of HHV-6A was isolated from the fluid specimens from glioma cysts. High levels of interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor α, and transforming growth factor β (TGF-β) were detected in the cyst fluid specimens from HHV-6-positive patients with glioma. Furthermore, HHV-6A infection promoted IL-6, IL-8, and TGF-β production in astrocyte cultures. Our studies strongly suggest the involvement of HHV-6 infection in the pathogenesis of glioma.
    The Journal of Infectious Diseases 09/2012; 206(9):1394-8. · 5.85 Impact Factor
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    ABSTRACT: Human herpesvirus-6 (HHV-6) is an important immunosuppressive and immunomodulatory virus that primarily infects immune cells (mainly CD4(+) T cells) and strongly suppresses the proliferation of infected cells. Toll-like receptors are pattern-recognition receptors essential for the development of an appropriate innate immune defense against infection. To understand the role of CD4(+) T cells in the innate response to HHV-6 infection and the involvement of TLRs, we used an in vitro infection model and observed that the infection of CD4(+) T cells resulted in the activation of JNK/SAPK via up-regulation of toll-like receptor 9 (TLR9). Associated with JNK activation, annexin V-PI staining indicated that HHV-6A was a strong inducer of apoptosis. Apoptotic response associated cytokines, IL-6 and TNF-α also induced by HHV-6A infection.
    Virology 11/2011; 422(1):92-8. · 3.35 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is a subdominant antigen expressed in EBV-associated malignancies, such as Hodgkin's diseases (HD) and nasopharyngeal carcinoma. A large number of previous studies have described LMP2A as an ideal target antigen in immunotherapy of EBV-related diseases, while limited successes have been achieved in clinical trials. Mycobacterium tuberculosis heat shock protein 70 (MtHsp70) is known as an effective molecular adjuvant for protein- or epitope-based vaccines. In the present study, we reconstituted two chaperone complexes of MtHsp70 and LMP2A-derived peptides (LMP2A(356-364) FLYALALLL and LMP2A(426-434) CLGGLLTMV) in vitro. We then investigated LMP2A-specific immune responses induced by reconstituted complexes of MtHsp70 and LMP2A-peptides using both EBV infected healthy donor PBMCs and HLA-A2.1 transgenic mouse models. We found that reconstituted complexes of MtHsp70 and LMP2A-peptides significantly elicit LMP2A-specific IFN-γ-producing cells and rousted cytotoxic T lymphocytes (CTLs) in vitro and in vivo. In addition, LMP2A-specific immune responses induced by the reconstituted complexes of MtHsp70 and LMP2A-peptides mediated potently protective activity as well as therapeutic efficacy against LMP2A-expressed tumor challenge in mouse models. These studies provide new insights for the development of novel LMP2A-based vaccines against EBV-associated malignancies.
    Vaccine 07/2011; 29(43):7414-23. · 3.77 Impact Factor
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    ABSTRACT: Interleukin-22 (IL-22), one of the cytokines secreted by T helper 17 (Th17) cells, was recently reported to be a novel inflammation driver through STAT3 signaling activation. We aimed to investigate the role of IL-22 expression in hepatocellular carcinoma (HCC). We demonstrated significant up-regulation of IL-22 in human HCC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, IL-22 expression was significantly higher in Edmondson Grade III-IV HCC patients versus Grade I-II, confirmed by both real-time polymerase chain reaction and immunohistochemistry. Both IL-22 receptor α and IL-23 were highly expressed in HCC and adjacent cirrhotic tissues compared to normal controls. Enhanced tumor growth and metastasis was found in mice that underwent subrenal transplantation of MHCC-97H cells cotransplanted with IL-22+ TILs cells. STAT3 phosphorylation and up-regulation of downstream genes Bcl-2, Bcl-XL, CyclinD1, and vascular endothelial growth factor (VEGF) promoted tumor growth and metastasis. In vitro studies confirmed the tumor-promoting and antiapoptotic effect of IL-22, as well as IL-6. In the mouse chronic hepatitis and HCC model, sustained and increased IL-22 expression and STAT3 activation were found in liver tissues. A linear correlation was demonstrated between IL-22 expression and hepatic complementary proliferation. An in vivo diethyl-nitrosamine-induced mouse HCC model verified that tumor formation was significantly decreased in IL-22 knockout mice. Conclusion: Excessive IL-22 can be found in the HCC microenvironment, leading to tumor growth, inhibition of apoptosis, and promotion of metastasis due to STAT3 activation.
    Hepatology 06/2011; 54(3):900-9. · 12.00 Impact Factor
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    ABSTRACT: Transduction of latent membrane protein 2 (LMP2)-specific T-cell receptors into activated T lymphocytes may provide a universal, MHC-restricted mean to treat EBV-associated tumors in adoptive immunotherapy. We compared TCR-specific promoters of distinct origin in lentiviral vectors, that is, Vβ6.7, delta, luria, and Vβ5.1 to evaluate TCR gene expression in human primary peripheral blood monocytes and T cell line HSB2. Vectors containing Vβ 6.7 promoter were found to be optimal for expression in PBMCs, and they maintained expression of the transduced TCRs for up to 7 weeks. These cells had the potential to recognize subdominant EBV latency antigens as measured by cytotoxicity and IFN-γ secretion. The nude mice also exhibited significant resistance to the HLA-A2 and LMP2-positive CNE tumor cell challenge after being infused with lentiviral transduced CTLs. In conclusion, LMP2-specific CTLs by lentiviral transduction have the potential use for treatment of EBV-related tumors.
    Clinical and Developmental Immunology 01/2011; 2011:716926. · 3.06 Impact Factor
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    ABSTRACT: Epstein-Barr virus infection is strongly associated with a number of malignancies. The EBV latent membrane protein 2A has been implicated as one of the most attractive candidates for immunotherapy of related malignancies. In previous studies, the T cell epitopes of LMP2A have been identified systematically. However, the epitope-based vaccine generally meets inefficient immunogenicity when used in vivo directly, which could be overcome by combination with appropriate adjuvants. Heat shock protein is a natural chaperon, which is able to activate the classical major histocompatibility complex class I antigen-processing pathway (cross-presentation). In this study, a minigene encoding LMP2A(356-364) (FLYALALLL) was genetically fused to the carboxy-terminal of mycobacterial heat shock protein 70. The epitope fusion protein was expressed and purified, and the cross-presentation of LMP2A(356-364) by monocyte-derived dendritic cells pulsed with the epitope fusion protein was evaluated. Results showed that the epitope fusion protein-pulsed mDCs were much more efficient than the single peptide-pulsed mDCs on CTL activation. Immunization of HLA-A2.1 transgenic mice with MtHsp70-LMP2A(356-364) generated peptide specific CTL more effectively than a single peptide plus incomplete Freund's adjuvant (IFA). Growth of LMP2A expressing B16 melanoma tumor cells was suppressed in the vaccinated groups. Our results suggested that MtHsp70-LMP2A(356-364) fusion protein was more effective than the CD8(+) T cell epitope alone on anti-tumor immunity. As a result, the MtHsp70-LMP2A(356-364) fusion protein is considered to be a promising candidate vaccine for EBV related malignancies.
    Cellular & molecular immunology 12/2009; 6(6):423-31. · 3.42 Impact Factor
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    ABSTRACT: To clone EBV-LMP2A gene, construct and identify the recombinant retroviral vector and stable cell strains expressing EBV LMP2A. The full-length EBV LMP2A gene was generated by RT-PCR amplification from B95.8 cells which contain complement nucleotide sequence of EBV LMP2A gene. The gene was ligated to T-vector and sequenced to construct retroviral vector consisting with LMP2A. To produce retroviral virus, packing cells, 293T cells were co-transfected with recombinant retroviral expression vector pGEZ-LMP2A and two auxiliary viral vectors pHIT456 and pHIT60 by lipofectAMINE2000. Viral titration was performed according to the instructions of the manufacturer. To establish L929 cell line stable expressing LMP2A, L929 cells were infected with recombinant retrovirus three times and selected by Zeocine. The Zeocine-resistant clones (L929/LMP2A) were screened for LMP2A expression by RT-PCR and Western blot. The recombinant retrovirus vector carrying LMP2A gene was constructed successfully. Transfection yield a titer of 5 x 10(8) infectious particles/L. The infected L929 cells were selected by Zeocine. Results of RT-PCR and Western blot indicated that L929 transgenetic cells could stably express EBV-LMP2A. The L929 cell line stably expressing LMP2A provides suitability for extraction of the LMP2A protein and preparations of the vaccine for the therapy of EBV-associated diseases.
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 11/2009; 25(11):1013-5.
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    ABSTRACT: Type II Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma and non-Hodgkin's lymphomas consistently express latent membrane 2A (LMP2A) proteins, which have been suggested to be an ideal target for immunotherapy. In previous studies we have demonstrated that using LMP2A protein loaded dendritic cells, the most powerful antigen processing cells in the body can elicit specific and robust anti-tumor cellular immune response in vitro. In this paper, we further investigated the T cell profile of the anti-tumor immune response. We found that LMP2A specific CD4+ and CD8+ T cells could be stimulated by LMP2A protein loaded dendritic cells (DCs). The Th1 type immune response is dominant in the immune response mediated by LMP2A specific CD4+ T cells. The CD8+ cytotoxic T cells can lyse LMP2A bearing cells effectively and specifically. The CD8+ cytotoxic T cells can also secrete high level of intracellular IFN-gamma, which indicates these cells are EBV-LMP2A specific cytotoxic T cells. Altogether, our studies proved that LMP2A protein loaded DCs can elicit anti-tumor cellular immune responses efficiently. This study provides a rationale for the DC-based immunotherapy against EBV-LMP2A expressing malignancies.
    Cellular & molecular immunology 09/2009; 6(4):269-76. · 3.42 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC) is a high incidence tumor in Southeast Asia. Among EBV encoded proteins, latent membrane protein 2A (LMP2A) is an important antigen for T cell therapy of EBV. In this study, we predicted six HLA-A2 restricted CTL candidate epitopes of LMP2A by SYFPEITHI, NetMHC and MHCPred methods combined with the polynomial method. Subsequently, biological functions of these peptides were tested by experiments in vitro. In ELISPOT assay, the positive response of the LMP2A specific CTL stimulated by three (LMP2A(264-272), LMP2A(426-434) and LMP2A(356-364)) of six peptides respectively showed that the numbers of spots forming cells (SFC) ranged from 55.7 to 80.6 SFC/50,000 CD8(+) T cells and the responding index (RI) ranged from 5.4 to 7. These three epitope-specific CTLs could effectively kill specific HLA-A2-expressing target cells. As a result, LMP2A(264-272) (QLSPLLGAV), LMP2A(426-434) (CLGGLLTMV) and LMP2A(356-364) (FLYALALLL) were identified as LMP2A-specific CD8(+) T-cell epitopes. It would be useful to clarify immune response toward EBV and to develop a vaccine against EBV-correlative NPC.
    Cellular & molecular immunology 05/2009; 6(2):97-103. · 3.42 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV), a potential oncogenic herpesvirus, has been found to be associated with several malignancies. It's critical to elicit cellular immunity of the body to fight against EBV-associated tumor development. Using dendritic cells (DCs) loaded with latent membrane protein 2A (LMP2A) to elicit T cell response against tumor may be one of the most direct and safest immunotherapy approaches. The present study aimed to develop DCs-based cancer vaccine (DC loaded with LMP2A protein) and study its biological characteristics and immune functions. Purified LMP2A protein was extracted from a cell line L929/LMP2A stably expressing LMP2A. LMP2A could be loaded on DCs with no significant changes of the DC surface markers and cytomorphology. The percentage of DCs loaded with LMP2A was above 80%. LMP2A-loaded DCs markedly enhanced the proliferation of antigen-specific CD8+ T and CD4+ T cells by 3H-TdR incorporation assay. Besides, the specific cytotoxicity of the CTLs against LMP2A target cells was also significantly increased. These results indicated that DC-based vaccine loaded with virus antigen could elicit potent CTL response and provide a foundation for further study on the DC-based immunotherapy for nasopharygeal carcinoma and other EBV associated tumors.
    Cellular & molecular immunology 11/2008; 5(5):365-72. · 3.42 Impact Factor
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    ABSTRACT: Human herpesvirus-6 (HHV-6) infection normally persists for the lifetime of the host and may reactivate with immunosuppression. The mechanism behind HHV-6 latent infection is still not fully understood. In this study, we observed that decreased proliferation of CD4+ T cells and PBMCs but not CD8+ T cells from HHV-6-infected individuals was stimulated with HHV-6-infected cell lysates. Moreover, HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals have suppressive activity on naïve CD4+ T and CD8+ T cells from HHV-6-uninfected individuals. However, no increased proportion of CD4+ CD25+ Treg cells from HHV-6-infected individuals contributed to the suppressive activity of the HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals. Transwell experiments, ELISA and anti-IL-10 antibody blocking experiment demonstrated that IL-10 may be the suppressive cytokine required for suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interleukin (IL)-10 and IL-4 further implicated the HHV-6-specific IL-10-producing CD4+ T cells in the suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interferon (IFN)-gamma demonstrated a decreased frequency of HHV-6-specific IFN-gamma-producing CD4+ T, but not CD8+ T cells in HHV-6-infected individuals, indicating that it was the CD4+ Th1 responses in HHV-6-infected individuals that were selectively impaired. Our findings indicated that HHV-6-specific IL-10-producing CD4+ T cells from HHV-6-infected individuals possess T regulatory type 1 cell activity: immunosuppression, high levels of IL-10 production, with a few cells expressing IFN-gamma, but none expressing IL-4. These cells may play an important role in latent HHV-6 infection.
    Microbiology and Immunology 02/2006; 50(10):787-803. · 1.55 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV) associated malignancies with a Type II latency gene expression pattern, such as Hodgkin's disease, and nasopharyngeal carcinoma (NPC), frequently express the EBV antigen latent membrane protein 2A (LMP2A). We expected to establish a highly expressing LMP2A yeast cell strain and get the high quality LMP2A protein, which was used for detection, analysis and characterization of its antibodies in various patients' sera of EBV associated malignancies. The plasmid pPICZalphaA-LMP2A containing the full length of LMP2A cDNA was constructed and transformed to Pichia pastoris GS115 to express LMP2A protein. After fermentation and purification, the LMP2A protein was used as an antigen to detect anti-LMP2A antibodies (Abs) in the sera of patients with EBV-associated malignancies in enzyme linked immunosorbent assay (ELISA) or Western-blot. LMP2A was expressed successfully with an expected molecular weight of approximately 54 kD and Abs to LMP2A were strikingly specific to NPC. Two-thirds or more sera from NPC patients were positive for anti-LMP2A immunoglobulin G (IgG) Abs. The antibodies were absent from the sera of other EBV-associated diseases except a small fraction of the gastric carcinoma. Comparing anti-viral capsid Ags (VCA) IgA and LMP2A IgA titers in the sera from 76 NPC patients, only 55% were positive for anti-LMP2A IgA Abs while 70% were positive for anti-VCA IgA. However, we found that 3 sera negative for VCA IgA were positive for LMP2A IgA. The results suggested the potential significance of LMP2A specific Abs for the diagnosis of EBV-associated malignancies, especially NPC.
    Chinese medical journal 06/2005; 118(9):725-30. · 0.90 Impact Factor
  • Hua Sun, Kun Yao, Yun Chen, Feng Zhou
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    ABSTRACT: Dendritic cells (DCs) are the most powerful antigen-presenting cells to induce specific T-cell immunity, which plays an important role in the body's anti-tumor responses. In this study, we assessed the feasibility and efficacy of inducing T-cell immunity against Epstein-Barr virus (EBV)-associated tumors in vivo using dendritic cells transfected with EBV latent membrane 2A (LMP2A) recombinant adenovirus. Cytokine-activated bone marrow-derived DCs transfected with EBV LMP2A recombinant adenovirus were infused into BALB/c mice. Splenic cytotoxic T-cell responses were evaluated by cytotoxicity and interferon-gamma production assays. in vivo immune protection was then assessed in the mice tumor models implanted with tumor cells expressing EBV LMP2A. DCs transfected with EBV LMP2A recombinant adenovirus could strongly induce EBV LMP2A-specific cytotoxic T-cell responses and upregulate interferon-gamma production in vivo. Vaccination using these DCs led to prolongation of overall survival rates in the mice tumor models and retarded tumor growth. The results suggest that DCs transfected with EBV LMP2A recombinant adenovirus can serve as a feasible and effective tool for eliciting LMP2A-specific cytotoxic T-cell responses against EBV LMP2A in vivo in the treatment of EBV-associated tumors.
    Chinese medical journal 11/2004; 117(10):1558-63. · 0.90 Impact Factor