曹雪涛
主要研究方向是以树突状细胞为重点的基础免疫学和新基因的发现及免疫新分子功能的研究、肿瘤免疫治疗和基因治疗的基础与临床研究。
个性化签名
- 姓名:曹雪涛
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学术头衔:
博士生导师, 中国工程院院士, “973”、“863”首席科学家, 国家杰出青年科学基金获得者
- 职称:-
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学科领域:
肿瘤学
- 研究兴趣:主要研究方向是以树突状细胞为重点的基础免疫学和新基因的发现及免疫新分子功能的研究、肿瘤免疫治疗和基因治疗的基础与临床研究。
男,1964年生,教授,博士生导师。国家免疫学重点学科带头人,国家杰出青年科学基金获得者,国家973免疫学项目首席科学家,“十五”863计划生物技术与现代农业领域专家,任中国免疫学会肿瘤免疫与生物治疗专业委员会主任委员、中国青年科协副主席、《中国肿瘤生物治疗杂志》主编等。主要研究方向是以树突状细胞为重点的基础免疫学和新基因的发现及免疫新分子功能的研究、肿瘤免疫治疗和基因治疗的基础与临床研究。在国内完成的工作以通讯作者在Nat Immunol、Blood、J Immunol、Cancer Res、JBC等SCI收录杂志发表论文101篇(影响因子>5分有27篇,其中10分以上6篇、 28分一篇),主编专著3部,是国家973免疫学项目及国家自然科学基金重大项目的负责人。以第一完成人获国家自然科学二等奖(2003)、上海市科技进步一等奖(2001)、军队科技进步一等奖(1998)、军队科技进步二等奖(1992,1999),以第一申请人申报国家发明专利16项,合作申请27项, 已经获得授权13项。牵头研制的4种生物高技术产品已试用于临床(其中2种已获国家新药证书)。30余次应邀赴国外作专题学术报告。
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曹雪涛, Hongmei Xu‡, Huazhang An‡, Yizhi Yu, Minghui Zhang, Runzi Qi, and Xuetao Cao§
Vol. 278, No.38, Issue of September 19, pp. 36334-36340, 2003 Printed in U.S.A.,-0001,():
-1年11月30日
CpG oligodeoxynucleotides (ODN) activate immune cells to produce immune mediators by Toll-like receptor 9 (TLR9)-mediated signal transduction, which activates mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) through the MyD88/IRAK/TRAF6 kinases cascade. However, the precise mechanisms of CpG ODN activation of immune cells have not been fully elucidated. The small GTP-binding protein Ras mediates MAPK activation in response to a variety of stimuli. Up to now, it is not clear whether Ras plays a role in CpG ODN signaling. In the present study, we found that the dominant-negative version of Ras (RasN17) and specific Ras inhibitor, FTI-277, inhibited CpG ODN-induced nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production by murine macrophage cell line RAW264.7. While overexpression of wild-type Ras enhanced CpG ODN-induced extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and NF-κB activation, overexpression of RasN17 inhibited CpG ODNinduced ERK, JNK, and NF-κB activation. RasN17 overexpression also inhibited CpG ODN-induced IRAK1/TRAF6 complex formation. Further studies revealed that CpG ODN activated Ras in a time-and dose-dependent manner, and Ras associated with TLR9 in a CpG ODN-dependent manner. Most interestingly, activation of Ras preceded the association of Ras with TLR9, giving rise to a possibility that Ras activation might not be dependent on the interaction between Ras and TLR9. Our data demonstrate for the first time that Ras can be activated by CpG ODN in macrophages, and Ras is involved in CpG ODN signaling as an early event by associating with TLR9 and promoting IRAK1/TRAF6 complex formation, and MAPK and NF-κB activation.
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曹雪涛, Lianjun Yang‡, Nan Li‡, Chunmei Wang, Yizhi Yu, Liang Yuan, Minghui Zhang, and Xuetao Cao§
Vol. 79, No.12, Issue of March 19, pp. 11639-11648, 2004 Printed in U.S.A.,-0001,():
-1年11月30日
We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcriptional regulation via phosphorylation of the C-terminal domain of RNA polymerase Ⅱ. The cyclin L2 protein contains an N-terminal "cyclin box" and C-terminal dipeptide repeats of alternating arginines and serines, a hallmark of the SR family of splicing factors. A new isoform and the mouse homologue of human cyclin L2 have also been cloned in this study. Human cyclin L2 is expressed ubiquitously in normal human tissues and tumor cells. We show here that cyclin L2 co-localizes with splicing factors SC-35 and 9G8 within nuclear speckles and that it associates with hyperphosphorylated, but not hypophosphorylated, RNA polymerase Ⅱ and CDK p110 PITSLRE kinase via its N-terminal cyclin domains. It can also associate with the SC-35 and 9G8 through its RS repeat region. Recombinant cyclin L2 protein can stimulate in vitro mRNA splicing. Overexpression of human cyclin L2 suppresses the growth of human hepatocellular carcinoma SMMC 7721 cells both in vitro and in vivo, inducing cellular apoptosis. This process involves up-regulation of p53 and Bax and decreased expression of Bcl-2. The data suggest that cyclin L2 represents a new member of the cyclin family, which might regulate the transcription and RNA processing of certain apoptosis-related factors, resulting in tumor cell growth inhibition and apoptosis.
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曹雪涛, Xiaojian Wang‡§, Nan Li§¶, Bin Liu¶, Hongying Sun‡, Taoyong Chen¶, Hongzhe Li‡, Jianming Qiu‡, Lihuang Zhang‡, Tao Wan¶, and Xuetao Cao‡¶Ⅱ
Vol. 279, No.44, Issue of October 29, pp. 45855-45864, 2004 Printed in U.S.A.,-0001,():
-1年11月30日
The phosphatidylethanolamine (PE)-binding proteins (PEBPs) are an evolutionarily conserved family of proteins with pivotal biological functions. Here we describe the cloning and functional characterization of a novel family member, human phosphatidylethanolaminebinding protein 4 (hPEBP4). hPEBP4 is expressed in most human tissues and highly expressed in tumor cells. Its expression in tumor cells is further enhanced upon tumor necrosis factor (TNF) α treatment, whereas hPEBP4 normally co-localizes with lysosomes, TNFαstimulation triggers its transfer to the cell membrane, where it binds to Raf-1 and MEK1. L929 cells overexpressing hPEBP4 are resistant to both TNFα-induced ERK1/2, MEK1, and JNK activation and TNFα-mediated apoptosis. Co-precipitation and in vitro protein binding assay demonstrated that hPEBP4 interacts with Raf-1 and MEK1. A truncated form of hPEBP4, lacking the PE-binding domain, maintains lysosomal co-localization but has no effect on cellular responses to TNFα. Given that MCF-7 breast cancer cells expressed hPEBP4 at a high level, small interfering RNA was used to silence the expression of hPEBP4. We demonstrated that down-regulation of hPEBP4 expression sensitizes MCF-7 breast cancer cells to TNFα-induced apoptosis. hPEBP4 appears to promote cellular resistance to TNF-induced apoptosis by inhibiting activation of the Raf-1/MEK/ERK pathway, JNK, and PE externalization, and the conserved region of PE-binding domain appears to play a vital role in this biological activity of hPEBP4.
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曹雪涛, J.-S. Qiu a, *, F. Zhang a, Y. Zhou a, H.-M. Han a, D.-S. Hu b, S.C. Tsang c, P.J.F. Harris c
Fuel 81(2002)1509-1514,-0001,():
-1年11月30日
Carbon nanotubes (CNTs) have been successfully produced from 10 typical Chinese caking-coals using an arc plasma technique. For comparison, one caking coal from New Zealand is also tested. The results show that all coals tested can be used to produce significant quantities of CNTs with fullerenes as by-products. The CNTs are examined using scanning electron microscope and high resolution transmission electron microscope. It has been found that the yields of CNTs are closely related to coal properties. The CNT yield increases as the fixed carbon content in coal increases or as the volatile matter content in coal decreases.
Carbon nanotubes, Preparation, Coal
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曹雪涛, Dian Wen Ju, Qun Tao, Guoliang Lou, Min Bai, Long He, Yili Yang, and Xuetao Cao
CANCER RESEARCH 61, 3735-3740, May 1, 2001,-0001,():
-1年11月30日
Dendritic cell (DC)-based tumor vaccine represents a promising approach to the immunotherapy of malignant tumors. We prepared a novel type of DC-based vaccine, stable conjugates of DCs and EL4 cells transduced with cDNA of OVA (E.G7). Immunization with DC-E.G7 conjugates led to generation of T helper (Th) 1 cytokine-producing cells, antigen-specific CD8+T cells, and strong antitumor immunity that is dependent on both CD4+T cells and CD8+T cells. To further increase the potency of the vaccine, interleukin l8-transfected DCs were used to prepare the ILl8DC-E.G7 conjugates. Immunization with such conjugates significantly increased the production of Thl cytokine-producing cells and the number of antigen-specific CD8+T cells, as well as stronger antitumor immunity. Furthermore, the increased Thl cytokine production and stronger antitumor effect were not observed in mice depleted of IFN-γ. These data indicated that DC-tumor cell conjugates are a potent tumor vaccine. Interleukin l8 can be administrated using gene-transfected cells and enhances antitumor immunity, which is mainly mediated by IFN-γ.
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曹雪涛, Runzi Qi, , Huazhang An, Yizhi Yu, Minghui Zhang, Shuxun Liu, Hongmei Xu, Zhenghong Guo, Tao Cheng, and Xuetao Cao
CANCER RESEARCH 63, 8323-8329, December 1, 2003,-0001,():
-1年11月30日
Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis; hence, perturbed Notch signaling may contribute to tumorigenesis. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in Africa and Asia. The mechanisms that orchestrate the multiple oncogenic insults required for initiation and progression of HCC are not clear. We constitutively overexpressed active Notch1 in human HCC to explore the effects of Notch1 signaling on HCC cell growth and to investigate the underlying molecular mechanisms. We show here that overexpression of Notch1 was able to inhibit the growth of HCC cells in vitro and in vivo. Biochemical analysis revealed the involvement of cell cycle regulated proteins in Notch1-mediated G0/G1 arrest of HCC cells. Compared with green fluorescent protein (GFP) control, transient transfection of Notch1 ICN decreased expression of cyclin A (3.5-fold), cyclin D1 (2-fold), cyclin E (4.5-fold), CDK2 (2.8-fold), and the phosphorylated form of retinoblastoma protein (3-fold). Up-regulation of p21waf/cip1 protein expression was observed in SMMC7721-ICN cells stably expressing active Notch1 but not in SMMC7721-GFP cells, which only express GFP. Furthermore, a 12-fold increase in p53 expression and an increase (4.8-fold) in Jun-NH2-terminal kinase activation were induced in SMMC7721-ICN cells compared with SMMC7721-GFP cells. In contrast, expression of the antiapoptotic Bcl-2 protein could not be detected in SMMC7721-ICN cells. These findings suggest that Notch1 signaling may participate in the development of HCC cells, affecting multiple pathways that control both cell proliferation and apoptosis.
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曹雪涛, Zhenhong Guo, Minghui Zhang, Huazhang An, Weilin Chen, Shuxun Liu, Jun Guo, Yizhi Yu, and Xuetao Cao
Blood. 2003; 102: 4441-4447,-0001,():
-1年11月30日
The mechanisms that underpin the intriguing capacity of Fas ligation on dendritic cells (DCs) to induce maturation and activation, rather than apoptosis, remain unclear. In the present study we confirm that Fas signaling induces both phenotypic and functional maturation of murine DCs, and we demonstrate that phenotypic maturation is associated with phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, activation of caspase-1, and secretion of interleukin-β(IL-1β). Specific inhibition of ERK1/2 diminished Fas ligation-induced caspase-1 activation, IL-1β secretion, and ensuing up-regulation of developmental markers, whereas treatment with neutralizing anti-IL-1β antibody abrogated phenotypic and functional maturation, indicating that IL-1βmediates Fas ligation-induced DC maturation in an autocrine manner. NF-κB activation was responsible for maintaining DC viability after Fas ligation. Inhibiting NF-κB did not affect either IL-1β secretion or phenotypic maturation but rather sensitized DCs to Fas-mediated apoptosis. In conclusion, positive signals originating from Fas are transduced through at least 2 different intracellular pathways in DCs, promoting not only survival but also an increase in maturation that correlates with increased antigen-presentation capability.
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曹雪涛, Taoyong Chen, Jun Guo, Mingjin Yang, Chaofeng Han, Minghui Zhang, Wei Chen, Qiuyan Liu, Jianli Wang, and Xuetao Cao
Blood. 2004; 103: 413-421,-0001,():
-1年11月30日
Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3β (MIP-3β) and induces them to retain responsiveness to MIP-1α after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsAmediated immunosuppression.
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曹雪涛, Tao Wan, Xiangyang Zhou, Guoyou Chen, Huazhang An, Taoyong Chen, Weiping Zhang, Shuxun Liu, Yingming Jiang, Feng Yang, Yanfeng Wu, and Xuetao Cao
Blood. 2004; 103: 1747-1754,-0001,():
-1年11月30日
Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit antitumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1β, tumor necrosis factor-α (TNF-α), and the chemokines IP-10, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and normal T cell expressed and secreted (RANTES). The induction of interferon-γ-inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin (OVA) 257-264 induces an OVA257-264specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.
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【期刊论文】Identification of an HLA-A*0201-restricted CD8+T-cell epitope SSp-1 of SARS-CoV spike protein
曹雪涛, Baomei Wang, Huabiao Chen, Xiaodong Jiang, Minghui Zhang, Tao Wan, Nan Li, Xiangyang Zhou, Yanfeng Wu, Feng Yang, Yizhi Yu, Xiaoning Wang, Ruifu Yang, and Xuetao Cao
Blood. 2004; 104: 200-206,-0001,():
-1年11月30日
Anovel coronavirus, severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike (S) protein is a major structural glycoprotein of the SARS virus and a potential target for SARS-specific cell-mediated immune responses. A panel of S protein-derived peptides was tested for their binding affinity to HLA-A*0201 molecules. Peptides with high affinity for HLA-A*0201 were then assessed for their capacity to elicit specific immune responses mediated by cytotoxic T lymphocytes (CTLs) both in vivo, in HLA-A2.1/Kb transgenic mice, and in vitro, from peripheral blood lymphocytes (PBLs) sourced from healthy HLAA2.1+donors. SARS-CoV protein-derived peptide-1 (SSp-1 RLNEVAKNL), induced peptide-specific CTLs both in vivo (transgenic mice) and in vitro (human PBLs), which specifically released interferon-γ (IFN-γ) upon stimulation with SSp-1-pulsed autologous dendritic cells (DCs) or T2 cells. SSp-1-specific CTLs also lysed major histocompatibility complex (MHC)-matched tumor cell lines engineered to express S proteins. HLA-A*0201-SSp-1 tetramer staining revealed the presence of significant populations of SSp-1-specific CTLs in SSp-1-induced CD8+T cells. We propose that the newly identified epitope SSp-1 will help in the characterization of virus control mechanisms and immunopathology in SARS-CoV infection, and may be relevant to the development of immunotherapeutic approaches for SARS.
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