自体树突状细胞疫苗治疗乙型肝炎病毒感染者的免疫机制研究
|
摘要
第一章
HBcAg/HBeAg对人树突状细胞表型和功能的影响
目的
在已研究的HBsAg对体外培养的人自体树突状细胞治疗性疫苗表型和功能的影响基础上,研究HBcAg/HBeAg对体外培养的人自体树突状细胞治疗性疫苗表型和功能的影响。
方法
1、取20例健康志愿者外周静脉血,肝素抗凝,以密度梯度离心法分离淋巴细胞。以GM-CSF,IL-4刺激,常规培养获得DC。再分别加入TNF-α、HBcAg+TNF-α、HBeAg+TNF-α刺激后,依次分组为:mDC组、HBcAg+mDC组、HBeAg+mDC组。
2、在培养第10天检测各组树突状细胞的表型以及分泌的细胞因子IFN-γ和IL-12p70的变化。
3、mDC组、HBcAg+mDC组、HBeAg+mDC组树突状细胞诱导的自体悬浮淋巴细胞增殖效应:在培养第7天与自体悬浮淋巴细胞共培养5天,在培养结束前12h加入1μCi/孔3H甲基胸腺嘧啶,用液体闪烁计数仪检测树突状细胞诱导的自体悬浮淋巴细胞增殖效应(cpm值)。
4、mDC组、HBcAg+mDC组、HBeAg+mDC组树突状细胞体外诱导的淋巴细胞毒活性:以HepG2为靶细胞,在第13天以乳酸脱氢酶法,按CytoTox 96 Non-Radioactive Cytotoxicity Assay试剂盒说明书,检测树突状细胞体外诱导的淋巴细胞毒活性。
结果
1、分别加入TNF-α、HBcAg+TNF-α、HBeAg+TNF-α刺激后,在光镜下各组均可见大量具有树突样突起的悬浮细胞,成簇分布。观察发现HBcAg+mDC组的树突状细胞聚集最早最明显,凋亡较多,3天后细胞数量明显减少。
2、观察各组中树突状细胞CD83、CD86、HLA-ABC的水平: HBcAg+mDC组和HBeAg+mDC组高于mDC组(P<0.01); HBcAg+mDC组高于HBeAg+mDC组(P<0.01)。
3、HBcAg和HBeAg可显著增强mDC分泌IFN-γ、IL-12p70的量(P<0.01)。IL-12p70的分泌量HBcAg+mDC组低于HBeAg+mDC组。
4、HBcAg+mDC、HBeAg+mDC、mDC组树突状细胞体外诱导的混合淋巴细胞增殖和杀伤效应均较显著,与HBcAg、HBeAg、自体悬浮淋巴细胞增殖和杀伤效应相比有显著性差异(P<0.01)。HBcAg+mDC、HBeAg+mDC两组与mDC诱导组之间的增殖和杀伤效应也具有显著性差异(P<0.01)。
结论
1、树突状细胞作为治疗性疫苗在体外培养,受TNF-α、HBcAg+TNF-α、HBeAg+TNF-α刺激后会有不同程度的分化、成熟或凋亡。
2、随着树突状细胞的成熟,树突状细胞表达CD83、CD86、HLA-ABC的水平相应有不同程度的提高。
3、随着树突状细胞的成熟,其分泌的细胞因子IFN-γ、IL-12p70的量相应有不同程度的增加。
4、随着树突状细胞的成熟,其体外诱导的淋巴细胞增殖及杀伤功能均有不同程度的增强。
第二章IL-10,TNF-α对慢性乙型肝炎患者树突状细胞的影响
目的
研究IL-10和TNF-α对慢性乙型肝炎患者树突状细胞的分化与功能的影响。
方法
1、健康志愿者和慢性乙型肝炎患者各15例,取外周静脉血,分离获得外周血单个核细胞(PBMC),常规培养获得DC组。
2、培养期间用IL-10刺激的为imDC组;TNF-α刺激的为mDC组;先后用IL-10,TNF-α刺激的为imDC+TNF-α组。
3、各组收获细胞后分别检测反映DC成熟度的各种分子及其体外诱导的自体淋巴细胞增殖效应。
结果
1、源于慢性乙型肝炎患者的常规培养的DC在数量,HLA-A, B, C、HLA-DR、CD86表达,IL-12p70分泌及其诱导的淋巴细胞增殖效应,均低于健康者组(P<0.01)。
2、mDC组:源于慢性乙型肝炎患者的mDC与健康者mDC表达的HLA-DR、HLA-A, B, C、CD86比较无显著性差异;两组mDC诱导自体淋巴细胞增殖效应和分泌的IL-12p70均明显增加,比较有显著性差异(P<0.01)。
3、imDC组:两组imDC的HLA-A, B, C、HLA-DR、CD86较mDC组低表达,分泌的IL-12p70极低,不能强烈激活诱导淋巴细胞增殖效应,与常规培养DC组比较有显著性差异(P<0.01)。
4、imDC+ TNF-α组:加入TNF-α刺激后HLA-A, B, C、HLA-DR、CD86仍低表达,分泌的IL-12p70和淋巴细胞增殖效应仍较低。
5、健康对照组、慢性乙型肝炎组的上清夜中IL-21的ELISA检测值均较低,无显著性差异。
结论
1、慢性乙型肝炎患者DC经TNF-α刺激后可同健康者一样高表达HLA-DR,HLA-A, B, C,CD86,但分泌IL-12p70仍较低,考虑为等量采集静脉血经相同方法培养后慢性乙型肝炎组在悬浮细胞数量上明显少于健康对照组所致。实验结果说明慢性乙型肝炎患者DC的状态虽然存在缺陷但在TNF-α的刺激下仍可向成熟分化。
2、使用IL-10抑制DC的发育成熟结果表明慢性乙型肝炎患者DC的数量,表达HLA-DR、HLA-A, B, C、CD86,诱导的自体淋巴细胞增殖及分泌细胞因子与未用IL-10相比有一定差距。
3、IL-10抑制的树突状细胞再加入TNF-α仍能保持不成熟的状态,其表面共刺激分子在接受TNF-α刺激后仍低表达,但是否能在致病微生物等致病抗原的刺激下仍能保持抑制状态还有待进一步研究。
4、IL-10可有效抑制DC的成熟,在慢性乙型肝炎患者和健康者两组间无明显差异,说明慢性乙型肝炎患者的DC和健康者一样可进行调控,这是所有HBV感染者进行免疫治疗的基础。
chapter 1
HBV core and nuclear antigen can enhance the differation and function of human dendritic cells
Objective
Monocyte-derived dendritic cells (MoDCs) are a promising cellular adjuvant for effector immune responses against tumors and chronic viral infections, including HBV. Several factors can induce DC maturation and activation including microorganisms, bacterial and viral products and cytokines. HBV core and nuclear antigen(HBcAg and HBeAg) are the most important antigens of HBV. We thus endeavored to analyze the ability of these two antigens to enhance the maturition of human DCs and the secretion of IFN-γand IL-12p70 by activated DCs, and to evaluate the influence of HBcAg and HBeAg on Human DCs in the anti-HBV pathoimmunological mechanisms.
Methods
The DC populations were generated from peripheral blood mononuclear cells(PBMCs) derived from healthy donors and then pulsed with HBcAg and HBeAg respectively.Cell surface molecules, including CD83, CD86 and HLA-ABC, were analyzed with flow cytometry. Concentrations of IFN-γ,IL-12p70 in the supernatant were assayed by ELISA methods.
Results Upregulation of maturation-associated phenotypic markers ( human leucocyte antigen HLA-ABC, CD83, CD86 ) on Maturity Dendritic Cell(mDC) after 72 h HBcAg/HBeAg pulsing was observed. The lymphocyte proliferation, the cytotoxic activity,as well as the IFN-γand IL-12p70 secretion, were observed more sronger in the HBcAg and HBeAg pulsed DCs than in the mDCs non-stimulated. And, HBcAg is more powerful than HBeAg.
Conclusion
HBcAg and HBeAg can enhance the maturation and secretion of human dendritic cells,and can improve lympholeukocyte multiplication and cytotoxic T lymphocyte activity.
chapter 2
The influence of IL-10 and TNF-αon the regulation of human dendritic cells in chronic hepatitis B patients
Objective
To investigate the influence of IL-10 and TNF-αon the regulation of human dendritic cells in chronic hepatitis B(CHB) patients.
Methods
Monocytes were isolated from fresh peripheral blood of CHB patients by Ficoll-Hypaque density gradient centrifugation and cultured with plastic-adherence method. DCs were induced and proliferated from the monocytes with granulocyte-macrophage clony stimulating factor(GM-CSF) and interleukin-4(IL-4)for Seven days, and then cocultured with TNF-αand IL-10 respectively. Elements reflected the maturity of DC were detected. The lymphocyte proliferation, as well as the IL-12p70 secretion were observed.
Results
Up-regulation of maturation-associated phenotypic markers ( human leukocyte antigen: HLA-A, B, C, HLA-DR, CD86)on Maturity Dendritic Cells(mDC) after TNF-αpulsing was observed.The lymphocyte proliferation, as well as the IL-12p70 ,IL-21 secretion were observed more stronger in the TNF-αpulsed DCs than in the DCs non-stimulated(P<0.01).The secretion and expression of human leukocyte antigens, as well as the lymphocyte proliferation by DCs were inhibited while treated with IL-10.
Conclusion
The number, maturation and function of DCs from CHB patients were all lower than from healthy donors. But the DCs from CHB patients can be regulated effectively in vitro. TNF-αcan promote DC ripe for mDC, while IL-10 inhibit DCs’maturation.
HBcAg/HBeAg对人树突状细胞表型和功能的影响
目的
在已研究的HBsAg对体外培养的人自体树突状细胞治疗性疫苗表型和功能的影响基础上,研究HBcAg/HBeAg对体外培养的人自体树突状细胞治疗性疫苗表型和功能的影响。
方法
1、取20例健康志愿者外周静脉血,肝素抗凝,以密度梯度离心法分离淋巴细胞。以GM-CSF,IL-4刺激,常规培养获得DC。再分别加入TNF-α、HBcAg+TNF-α、HBeAg+TNF-α刺激后,依次分组为:mDC组、HBcAg+mDC组、HBeAg+mDC组。
2、在培养第10天检测各组树突状细胞的表型以及分泌的细胞因子IFN-γ和IL-12p70的变化。
3、mDC组、HBcAg+mDC组、HBeAg+mDC组树突状细胞诱导的自体悬浮淋巴细胞增殖效应:在培养第7天与自体悬浮淋巴细胞共培养5天,在培养结束前12h加入1μCi/孔3H甲基胸腺嘧啶,用液体闪烁计数仪检测树突状细胞诱导的自体悬浮淋巴细胞增殖效应(cpm值)。
4、mDC组、HBcAg+mDC组、HBeAg+mDC组树突状细胞体外诱导的淋巴细胞毒活性:以HepG2为靶细胞,在第13天以乳酸脱氢酶法,按CytoTox 96 Non-Radioactive Cytotoxicity Assay试剂盒说明书,检测树突状细胞体外诱导的淋巴细胞毒活性。
结果
1、分别加入TNF-α、HBcAg+TNF-α、HBeAg+TNF-α刺激后,在光镜下各组均可见大量具有树突样突起的悬浮细胞,成簇分布。观察发现HBcAg+mDC组的树突状细胞聚集最早最明显,凋亡较多,3天后细胞数量明显减少。
2、观察各组中树突状细胞CD83、CD86、HLA-ABC的水平: HBcAg+mDC组和HBeAg+mDC组高于mDC组(P<0.01); HBcAg+mDC组高于HBeAg+mDC组(P<0.01)。
3、HBcAg和HBeAg可显著增强mDC分泌IFN-γ、IL-12p70的量(P<0.01)。IL-12p70的分泌量HBcAg+mDC组低于HBeAg+mDC组。
4、HBcAg+mDC、HBeAg+mDC、mDC组树突状细胞体外诱导的混合淋巴细胞增殖和杀伤效应均较显著,与HBcAg、HBeAg、自体悬浮淋巴细胞增殖和杀伤效应相比有显著性差异(P<0.01)。HBcAg+mDC、HBeAg+mDC两组与mDC诱导组之间的增殖和杀伤效应也具有显著性差异(P<0.01)。
结论
1、树突状细胞作为治疗性疫苗在体外培养,受TNF-α、HBcAg+TNF-α、HBeAg+TNF-α刺激后会有不同程度的分化、成熟或凋亡。
2、随着树突状细胞的成熟,树突状细胞表达CD83、CD86、HLA-ABC的水平相应有不同程度的提高。
3、随着树突状细胞的成熟,其分泌的细胞因子IFN-γ、IL-12p70的量相应有不同程度的增加。
4、随着树突状细胞的成熟,其体外诱导的淋巴细胞增殖及杀伤功能均有不同程度的增强。
第二章IL-10,TNF-α对慢性乙型肝炎患者树突状细胞的影响
目的
研究IL-10和TNF-α对慢性乙型肝炎患者树突状细胞的分化与功能的影响。
方法
1、健康志愿者和慢性乙型肝炎患者各15例,取外周静脉血,分离获得外周血单个核细胞(PBMC),常规培养获得DC组。
2、培养期间用IL-10刺激的为imDC组;TNF-α刺激的为mDC组;先后用IL-10,TNF-α刺激的为imDC+TNF-α组。
3、各组收获细胞后分别检测反映DC成熟度的各种分子及其体外诱导的自体淋巴细胞增殖效应。
结果
1、源于慢性乙型肝炎患者的常规培养的DC在数量,HLA-A, B, C、HLA-DR、CD86表达,IL-12p70分泌及其诱导的淋巴细胞增殖效应,均低于健康者组(P<0.01)。
2、mDC组:源于慢性乙型肝炎患者的mDC与健康者mDC表达的HLA-DR、HLA-A, B, C、CD86比较无显著性差异;两组mDC诱导自体淋巴细胞增殖效应和分泌的IL-12p70均明显增加,比较有显著性差异(P<0.01)。
3、imDC组:两组imDC的HLA-A, B, C、HLA-DR、CD86较mDC组低表达,分泌的IL-12p70极低,不能强烈激活诱导淋巴细胞增殖效应,与常规培养DC组比较有显著性差异(P<0.01)。
4、imDC+ TNF-α组:加入TNF-α刺激后HLA-A, B, C、HLA-DR、CD86仍低表达,分泌的IL-12p70和淋巴细胞增殖效应仍较低。
5、健康对照组、慢性乙型肝炎组的上清夜中IL-21的ELISA检测值均较低,无显著性差异。
结论
1、慢性乙型肝炎患者DC经TNF-α刺激后可同健康者一样高表达HLA-DR,HLA-A, B, C,CD86,但分泌IL-12p70仍较低,考虑为等量采集静脉血经相同方法培养后慢性乙型肝炎组在悬浮细胞数量上明显少于健康对照组所致。实验结果说明慢性乙型肝炎患者DC的状态虽然存在缺陷但在TNF-α的刺激下仍可向成熟分化。
2、使用IL-10抑制DC的发育成熟结果表明慢性乙型肝炎患者DC的数量,表达HLA-DR、HLA-A, B, C、CD86,诱导的自体淋巴细胞增殖及分泌细胞因子与未用IL-10相比有一定差距。
3、IL-10抑制的树突状细胞再加入TNF-α仍能保持不成熟的状态,其表面共刺激分子在接受TNF-α刺激后仍低表达,但是否能在致病微生物等致病抗原的刺激下仍能保持抑制状态还有待进一步研究。
4、IL-10可有效抑制DC的成熟,在慢性乙型肝炎患者和健康者两组间无明显差异,说明慢性乙型肝炎患者的DC和健康者一样可进行调控,这是所有HBV感染者进行免疫治疗的基础。
chapter 1
HBV core and nuclear antigen can enhance the differation and function of human dendritic cells
Objective
Monocyte-derived dendritic cells (MoDCs) are a promising cellular adjuvant for effector immune responses against tumors and chronic viral infections, including HBV. Several factors can induce DC maturation and activation including microorganisms, bacterial and viral products and cytokines. HBV core and nuclear antigen(HBcAg and HBeAg) are the most important antigens of HBV. We thus endeavored to analyze the ability of these two antigens to enhance the maturition of human DCs and the secretion of IFN-γand IL-12p70 by activated DCs, and to evaluate the influence of HBcAg and HBeAg on Human DCs in the anti-HBV pathoimmunological mechanisms.
Methods
The DC populations were generated from peripheral blood mononuclear cells(PBMCs) derived from healthy donors and then pulsed with HBcAg and HBeAg respectively.Cell surface molecules, including CD83, CD86 and HLA-ABC, were analyzed with flow cytometry. Concentrations of IFN-γ,IL-12p70 in the supernatant were assayed by ELISA methods.
Results Upregulation of maturation-associated phenotypic markers ( human leucocyte antigen HLA-ABC, CD83, CD86 ) on Maturity Dendritic Cell(mDC) after 72 h HBcAg/HBeAg pulsing was observed. The lymphocyte proliferation, the cytotoxic activity,as well as the IFN-γand IL-12p70 secretion, were observed more sronger in the HBcAg and HBeAg pulsed DCs than in the mDCs non-stimulated. And, HBcAg is more powerful than HBeAg.
Conclusion
HBcAg and HBeAg can enhance the maturation and secretion of human dendritic cells,and can improve lympholeukocyte multiplication and cytotoxic T lymphocyte activity.
chapter 2
The influence of IL-10 and TNF-αon the regulation of human dendritic cells in chronic hepatitis B patients
Objective
To investigate the influence of IL-10 and TNF-αon the regulation of human dendritic cells in chronic hepatitis B(CHB) patients.
Methods
Monocytes were isolated from fresh peripheral blood of CHB patients by Ficoll-Hypaque density gradient centrifugation and cultured with plastic-adherence method. DCs were induced and proliferated from the monocytes with granulocyte-macrophage clony stimulating factor(GM-CSF) and interleukin-4(IL-4)for Seven days, and then cocultured with TNF-αand IL-10 respectively. Elements reflected the maturity of DC were detected. The lymphocyte proliferation, as well as the IL-12p70 secretion were observed.
Results
Up-regulation of maturation-associated phenotypic markers ( human leukocyte antigen: HLA-A, B, C, HLA-DR, CD86)on Maturity Dendritic Cells(mDC) after TNF-αpulsing was observed.The lymphocyte proliferation, as well as the IL-12p70 ,IL-21 secretion were observed more stronger in the TNF-αpulsed DCs than in the DCs non-stimulated(P<0.01).The secretion and expression of human leukocyte antigens, as well as the lymphocyte proliferation by DCs were inhibited while treated with IL-10.
Conclusion
The number, maturation and function of DCs from CHB patients were all lower than from healthy donors. But the DCs from CHB patients can be regulated effectively in vitro. TNF-αcan promote DC ripe for mDC, while IL-10 inhibit DCs’maturation.
引文
[1] WHO and CDC fact sheets.www.who.int and WWW.cdc.gov
[2] Lim CY, Kowdley KV[J]. Optimal duration of therapy in HBV-related cirrhosis. J Antimicrob Chemother. 2007 Jul;60(1):2~6
[3] Maurice R. Hilleman. Critical overview and outlook:pathogenesis, prevention,and treatment of hepatitis and hepatocarcinoma caused by hepatitis B virus[J].Vaccine. 2003,21:4626~4649
[4]卫生部.卫生统计年鉴[M].北京:中国协和医科大学出版社.2003
[5]姚光弼,任红,王宝恩,等.恩替卡韦治疗拉米夫定失败的慢性乙型肝炎患者多中心、随机、双盲对照临床研究[J].肝脏.2005,3(1):2~4
[6] Long JE, Huang LN, Qin ZQ,et al. IFN-gamma increases efficiency of DNA vaccine in protecting ducks against infection[J].World J Gastroenterol. 2005,11(32):4967~4973
[7] Marcellin P, Lau GK, Zeuzem S,et al.Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a[J].Liver Int.2008,28(4):477~485
[8] Escudero A, Rodriguez F, Serra MA, et al.Pegylated alpha-interferon-2a plus ribavirin compared with pegylated alpha-interferon-2b plus ribavirin for initial treatment of chronic hepatitis C virus: Prospective, non-randomized study[J].J Gastroenterol Hepatol.2008 Apr 19 [Epub ahead of print]
[9] Yuan Y, Iloeje U, Li H,et al. Economic implications of entecavir treatment in suppressing viral replication in chronic hepatitis B (CHB) patients in China from a perspective of the Chinese Social Security program.. Value Health.2008,1:S11~22
[10] Thermet A, Buronfosse T, Werle-Lapostolle B,et al.DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection[J].J Gen Virol.2008,89(Pt 5):1192~1201
[11] Veenstra DL, Spackman DE, Bisceglie A,et al. Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis[J]. Aliment Pharmacol Ther. 2008 Mar 27 [Epub ahead of print]
[12]张定凤.乙型肝炎抗病毒治疗的前瞻[J].中华肝脏病杂志.2006,14:483~488
[13] Xue-zhang Duan, Min Wang , Han-wei Li,et al. Decreased frequency and function of circulating plasmocytoid Dendritic cells(pDC) in Hepatitis B virus infected humans[J]. Journal of Immunology.2004,24(6): 637~646
[14] Hasebe A, Akbar SM, Furukawa S, et al.Impaired functional capacities of liver dendritic cells from murine hepatitis B virus (HBV) carriers: relevance to low HBV-specific immune responses[J].Clin Exp Immunol.2005,139(1):35~42
[15] Tavakoli S, Schwerin W, Rohwer A,et al. Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection[J].J Gen Virol. 2004,85(Pt 10):2829~2836
[16] Van der Molen RG, Sprengers D, Binda RS, et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B[J].Hepatology.2004,40(3): 738~746
[17] Akbar SM, Horiike N, Onji M, et al.Dendritic cells and chronic hepatitis virus carriers[J]. Intervirology. 2001,44(4):199~208
[18] Zheng BJ, Zhou J, Qu D, et al. Selective functional deficit in dendritic cell-T cell interaction is a crucial mechanism in chronic hepatitis B virus infection[J]. J Viral Hepat. 2004, 11(3):217~224
[19] French AR,Yokoyama WM.Natural killer cells and viral infections[J].Current Opinion in Immunology.2003,15(1): 45~51
[20] Hamerman JA, Ogasawara K, Lanier LL.NK cells in innate immunity[J].Current Opinion in Immunology.2005,17(1):29~35
[21] Hakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection[J].Science. 2004,305(5685):872~874
[22] Chen Y, Wei H, Sun R, et al. Impaired function of hepatic natural killer cells from murine chronic HBsAg carriers[J].Int Immunopharmacol.2005,5(13-14): 1839~1852
[23] Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection[J].Science.2004,305(5685): 872~874
[24]李用国,梁增伟,蔡大川,等.树突状细胞体外激活的CTL杀伤效应[J].重庆医科大学学报.2003, 28: 138~139
[25]李用国,陈敏,张大志,等.自体树突状细胞疫苗治疗慢性乙型肝炎的临床研究[J].中华肝脏病杂志.2003,11:206~208
[26] Cools N, Van Tendeloo VF, Smits EL, et al. Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4(+) regulatory T cells[J].J Cell Mol Med.2008 ,12(2):690~700
[27] Li M, Zhang X, Zheng X, et al. Tolerogenic dendritic cells transferring hyporesponsiveness and synergizing T regulatory cells in transplant tolerance[J]. Int Immunol.2008,20(2):285~293
[28] Lau AW, Biester S, Cornall RJ,et al. Lipopolysaccharide-activated IL-10 secreting dendritic cells suppress experimental autoimmune uveoretinitis by MHCII-dependent activation of CD62L-expressing regulatory T cells[J].J Immunol.2008,180(6):3889~3899
[29] Sousa-Canavez JM, Canavez FC, Leite KR, et al.Therapeutic Dendritic cell vaccine preparation using tumor RNA transfection:A promise approach to treat prostate cance[J].Genet Vaccines Ther.2008,6:2
[30] Royer PJ, Bougras G, Ebstein F,et al.Efficient monocyte-derived dendritic cell generation in patients with acute myeloid leukemia after chemotherapy treatment: Application to active immunotherapy[J].Exp Hematol.2008, 36(3):329~339
[31] Apewalis C, Jacobs B, Wuttke M,et al.IFN-{alpha} Skews Monocytes into CD56+-Expressing Dendritic Cells with Potent Functional Activities In Vitro and In Vivo[J].J Immunol.2008,180(3): 1462~1470
[32] Xiong SQ, Lin BL, Gao X, et al. IL-12 promotes HBV-specific central memory CD8+T cell responses by PBMCs from chronic hepatitis B virus carriers[J]. Int Immunopharmacol.2007,7(5):578~587
[33] Eichler H, Nguyen XD, Roelen D, et al. Multicenter study on in vitro characterization of dendritic cells[J].Cytotherapy. 2008,10(1):21~29
[34] Castellano G, Woltman AM, Schlagwein N, et al. Immune modulation of humandendritic cells by complement[J].Eur J Immunol.2007,37(10):2803~2811
[35] Repnik U, Bergant M, Wraber B, et al. Late dendritic cells are still able to evoke a potent alloreactive CTL response[J].Immunobiology.2008,213(1):51~64
[36] Pepper M, Dzierszinski F, Wilson E, et al. Plasmacytoid Dendritic Cells Are Activated by Toxoplasma gondii to Present Antigen and Produce Cytokines[J].J Immunol.2008,180(9):6229~6236
[37] Frasca L, Nasso M, Spensieri F, et al. IFN-{gamma} Arms Human Dendritic Cells to Perform Multiple Effector Functions[J].J Immunol.2008,180(3): 1471~1481
[38] Saito K, Ait-Goughoulte M, Truscott SM, et al. Hepatitis C virus inhibits cell surface expression of HLA-DR, prevents dendritic cell maturation and induces IL-10 production[J]. J Virol.2008,82(7):3320~3328
[39] Theiner G, Rossner S, Dalpke A, et al.TLR9 cooperates with TLR4 to increase IL-12 release by murine dendritic cells[J].Mol Immunol,2008,45(1):244~252
[40] Lehner M, Morhart P, Stilper A,et al.Efficient chemokine-dependent migration and primary and secondary IL-12 secretion by human dendritic cells stimulated through Toll-like receptors[J].J Immunother.2007,30(3):312~322
[41] Qiu SJ, Lu L, Qiao C, et al. Induction of tumor immunity and cytotoxicT lymphocyte responses using dendritic cells transduced by adenoviral vectors encoding HBsAg: comparison to protein immunization[J].J Cancer Res Clin Oncol 2005,131(7):429~438
[42] H?nig J, Lutz MB. Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing[J].J Immunol.2008,180(3): 1405~1413
[43]中华医学会肝病学分会、感染病学分会.慢性乙型肝炎防治指南[J].中华肝脏病杂志.2005,13(12):881~891
[44]中华医学会传染病与寄生虫病学分会,中华医学会肝病学分会.病毒性肝炎防治方案[J].中华传染病学杂志.2001,19(1):56~62
[45] Conroy H, Marshall NA, Mills KH. TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours[J].Oncogene. 2008,27(2):168~180
[46] Cools N, Ponsaerts P, Van Tendeloo VF, et al.Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector Tcells[J].J Leukoc Biol.2007,82(6):1365~1374
[47] Matsuda Y, Toda M, Kato T, et al.Fulminant liver failure triggered by therapeutic antibody treatment in a mouse model[J].Int J Oncol.2006,29(5): 1119~1125
[1] Steinman RM, Cohn ZA.Pillars Article: Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution[J].J Exp Med.1973,137:1142~1162
[2] Usharauli D.Dendritic cells and the immunity/tolerance decision[J].Med Hypotheses. 2005,64(1):112~113
[3] Errington F, Steele L, Prestwich R, et al.Reovirus Activates Human Dendritic Cells to Promote Innate Antitumor Immunity[J].J Immunol.2008,180(9): 6018~6026
[4] Guermonprez P, Amigorena S.An export-reimport model for cross presentation of particulate antigens by MHC class I molecules in dentritic cells[J].J Soc Biol.2004,198(2):121~122
[5] Ponsaerts P, Van den Bosch G, Cools N, et al.Messenger RNA electroporation of human monocytes, followed by rapid in vitro differentiation, leads to highly stimulatory antigen-loaded mature dendritic cells[J].J Immunol.2002,169(4): 1669~1675
[6] Cuellar A, Fonseca A, Gomez A.Effect of lipopolysaccharides on human dendritic cell cultures and its inhibition by polymyxin B[J].Biomedica. 2004,24(4):413~422
[7] Den Brok MH, Nierkens S, Figdor CG, et al. Dendritic cells: tools and targets for antitumor vaccination[J].Expert Rev Vaccines.2005,4(5):699~710
[8] Tsiatas ML, Gritzapis AD, Cacoullos NT, et al.A novel culture environment for generating mature human dentritic cells from peripheral blood CD14+ cells[J].Anticancer Res. 2001,21(2A):1199~1206
[9] Pepper M, Dzierszinski F, Wilson E, et al.Plasmacytoid Dendritic Cells Are Activated by Toxoplasma gondii to Present Antigen and Produce Cytokines[J].J Immunol.2008,180(9): 6229~6236
[10] Caux C, Dezutter-Dambuyant C, Schmitt D, et al.GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells[J].Nature.1992, 360(6401):258~261
[11] Colonna M,Trinchieri G,Liu YJ.Plasmacytoid dendritic cells in immunity[J].Nat Immunol.2004,5(12):1219~1226
[12] Wilson NS,EL-Sukkari D,Villadangos JA.Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by ericontrolling the rates of MHC classⅡsynthesis and endocytosis[J]. Blood,2004,103(6):2187~2195
[13] Parslow TG,Stites DP,Terr AL,Imboden JB[M].Medical Immunology.10thed. New York:McGrawHill,2000
[14] Smits EL, Ponsaerts P, Van de Velde AL, et al. Proinflammatory response of humanleukemic cells to dsRNA transfection linked to activation of dendritic cells[J].Leukemia. 2007,21(8):1691~1699
[15] Lamhamedi-Cherradi SE, Martin RE, Ito T, et al.Fungal Proteases Induce Th2 Polarization through Limited Dendritic Cell Maturation and Reduced Production of IL-12[J].J Immunol. 2008,180(9):6000~6009.
[16]陈智超,李菁媛,姚军霞,等.DC-CIK细胞治疗自体外周血造血干细胞移植后急性髓性白血病的临床研究[J].临床内科杂志.2007,24(9)596~598
[17] Ni HT,Spelman SR,Jean WC,et a1.Immunization with dendritic ceils pulsed with tumor extract increases survival of mice bearing intracranial gliomas[J].J Neurooncol,2001,51(1):1~9
[18] Ehtesham M,Kabos P,Gutierrez MA,et a1.Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity against malignant glioma in rats[J].J Immunother.2003,6(2):107~116
[19] Yamanaka R,Abe T,Yajima N,et a1.Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic ceils elicits immune responses:results of a clinical phase I/II trial[J].Br J Cancer,2003,89(7):1172~1179
[20]张韬,周新荣,牛洪泉,等.对负载人胶质瘤冻融抗原的树突状细胞功能的实验研究[J].中国临床神经外科杂志.2003,8(4):242~244
[21]薛德麟,雷霆,董震,等.脑胶质瘤自体疫苗的临床实验研究[J].中华实验外科杂志.2003,20(2):139~l40
[22] Kono K,Takahashi A,Sugai H,et al.Dendritic cells pulsed with HER-2/neu -derived peptides can induce specific T-cell responses in patients with gastric cancer[J]. Clin Cancer Res. 2002 ,8(11):3394~400
[23] Liau LM,Black KL,Prins RM,et a1.Treatment of in.tracranial gliomas with bone marrow-derived dendritic cels pulsed with tumor antigens[J].J Neurosurg,1999,90(6):1115~1124
[24]刘福生,王忠诚,厉俊华,等.肿瘤抗原致敏树突状细胞瘤苗治疗颅内胶质瘤的实验研究[J].中华神经外科杂志.2002,18(2):91~95
[25] Yu JS,Wheeler CJ,Zehzer PM,et a1.Vaccination of malignant glioma patients withpeptide-pulsed dendritic cels elicits systemic cytotoxicity and intracranial T celinfiltration [J].Cancer Res.2001,61:842~847
[26] Ribas A, Butterfield LH, Hu B, et al. Generation of T-cell immunity to a murine melanoma using MART-1-engineered dendritic cells[J].J Immunother. 2000,23(1):59~66
[27] Pecher G, Schirrmann T, Kaiser L,et al.Efficient cryopreservation of dendritic cells transfected with cDNA of a tumour antigen for clinical application[J]. Biotechnol Appl Biochem.2001, 34 (Pt 3):161~162
[28] Pecher G, H?ring A, Kaiser L,et al.Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial[J].Cancer Immunol Immunother. 2002 ,51(11-12):669~673
[29] Pecher G, Spahn G, Schirrmann T, et al.Mucin gene (MUC1) transfer into human dendritic cells by cationic liposomes and recombinant adenovirus[J].Anticancer Res.2001, 21(4A):2591~2596
[30] Pecher G, Finn OJ.Induction of cellular immunity in chimpanzees to human tumor-associated antigen mucin by vaccination with MUC-1 cDNA-transfected Epstein-Barr virus-immortalized autologous B cells[J].Proc Natl Acad Sci USA. 1996, 93(4):1699~1704
[31] Mach N, Gillessen S, Wilson SB, et al.Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony- stimulating factor or Flt3- ligand[J].Cancer Res.2000,60(12): 3239~3246
[32] Ju DW,Tao Q,Lou G,et al.Interleukin 18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates[J].Cancer Res.2001, 61(9):3735~3740
[33] Wang Q, Yu H, Ju DW,et al.Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma[J].Gene Ther.2001,8(7):542~550
[34] Ju DW, Yang Y, Tao Q, et al.Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity [J].Gene Ther.2000,7(19):1672~1679
[35] Zheng BJ, Zhou J, Qu D,et al.Selective functional deficit in dendritic cell--T cell interaction is a crucial mechanism in chronic hepatitis B virus infection [J].J Viral Hepat.2004,11(3):217~224
[36] Tavakoli S, Mederacke I, Herzog-Hauff S, et al. Peripheral blood dendritic cells are phenotypically and functionally intact in chronic hepatitis B virus (HBV) infection[J].Clin Exp Immunol.2008,51(1):61~70
[37] Zhang Z, Chen D, Yao J,et al.Increased infiltration of intrahepatic DC subsets closely correlate with viral control and liver injury in immune active pediatric patients with chronic hepatitis B.Clin Immunol[J].2007,122(2):173~180
[38] Untergasser A, Zedler U, Langenkamp A,et al.Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection[J]. Hepatology.2006,43(3):539~547
[39] Chen M, Li YG, Zhang DZ,et al.Therapeutic effect of autologous dendritic cell vaccine on patients with chronic hepatitis B: a clinical study[J].World J Gastroenterol.2005,11(12):1806~1808
[40]黄呈辉,欧阳玲,黄建国,等.HBV抗原基因修饰树突状细胞疫苗体外抗HBV的作用.世界华人消化杂志.2006,14(19):1864~1869
[41] Qiu SJ, Lu L, Qiao C,et al.Induction of tumor immunity and cytotoxic t lymphocyte responses using dendritic cells transduced by adenoviral vectors encoding HBsAg: comparison to protein immunization[J].J Cancer Res Clin Oncol.2005,131(7):429~438
[42] Kim YS, Yang SH, Kang HG,et al. Distinctive role of donor strain immature dendritic cells in the creation of allograft tolerance[J].Int Immunol. 2006,18(12):1771~1777
[43] Cools N, Van Tendeloo VF, Smits EL, et al.Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4(+) regulatory T cells[J].J Cell Mol Med.2008,12(2):690~700
[44] Cools N, Ponsaerts P, Van Tendeloo VF, et al.Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector Tcells[J].J Leukoc Biol.2007,82(6):1365~1374
[45] Shah PD, Gilbertson SM, Rowley DA. Dendritic cells that have interacted with antigen are targets for natural killer cells[J].J Exp Med. 1985,162(2):625~636
[46] Fernandez NC, Lozier A, Flament C, et al.Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo[J].Nat Med,1999,5(4):405~411
[47] Chiesa MD, Sivori S, Castriconi R, et al. Pathogen-induced private conversations between natural killer and dendritic cells[J].Trends Microbiol. 2005,13(3):128~136
[48] Gerosa F, Gobbi A, Zorzi P, et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions[J].J Immunol,2005,174(2):727~734
[49] Andrews DM, Andoniou CE, Scalzo AA, et al.Cross-talk between dendritic cells and natural killer cells in viral infection[J].Mol Immunol,2005, 42(4):547~555
[50] Kalinski P, Giermasz A, Nakamura Y,et al. Helper role of NK cells during the induction of anticancer responses by dendritic cells[J].Mol Immunol.2005, 42(4):535~539
[51] Piccioli D, Sbrana S, Melandri E,et al.Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells[J].J Exp Med.2002,195(3): 335~341
[2] Lim CY, Kowdley KV[J]. Optimal duration of therapy in HBV-related cirrhosis. J Antimicrob Chemother. 2007 Jul;60(1):2~6
[3] Maurice R. Hilleman. Critical overview and outlook:pathogenesis, prevention,and treatment of hepatitis and hepatocarcinoma caused by hepatitis B virus[J].Vaccine. 2003,21:4626~4649
[4]卫生部.卫生统计年鉴[M].北京:中国协和医科大学出版社.2003
[5]姚光弼,任红,王宝恩,等.恩替卡韦治疗拉米夫定失败的慢性乙型肝炎患者多中心、随机、双盲对照临床研究[J].肝脏.2005,3(1):2~4
[6] Long JE, Huang LN, Qin ZQ,et al. IFN-gamma increases efficiency of DNA vaccine in protecting ducks against infection[J].World J Gastroenterol. 2005,11(32):4967~4973
[7] Marcellin P, Lau GK, Zeuzem S,et al.Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a[J].Liver Int.2008,28(4):477~485
[8] Escudero A, Rodriguez F, Serra MA, et al.Pegylated alpha-interferon-2a plus ribavirin compared with pegylated alpha-interferon-2b plus ribavirin for initial treatment of chronic hepatitis C virus: Prospective, non-randomized study[J].J Gastroenterol Hepatol.2008 Apr 19 [Epub ahead of print]
[9] Yuan Y, Iloeje U, Li H,et al. Economic implications of entecavir treatment in suppressing viral replication in chronic hepatitis B (CHB) patients in China from a perspective of the Chinese Social Security program.. Value Health.2008,1:S11~22
[10] Thermet A, Buronfosse T, Werle-Lapostolle B,et al.DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection[J].J Gen Virol.2008,89(Pt 5):1192~1201
[11] Veenstra DL, Spackman DE, Bisceglie A,et al. Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis[J]. Aliment Pharmacol Ther. 2008 Mar 27 [Epub ahead of print]
[12]张定凤.乙型肝炎抗病毒治疗的前瞻[J].中华肝脏病杂志.2006,14:483~488
[13] Xue-zhang Duan, Min Wang , Han-wei Li,et al. Decreased frequency and function of circulating plasmocytoid Dendritic cells(pDC) in Hepatitis B virus infected humans[J]. Journal of Immunology.2004,24(6): 637~646
[14] Hasebe A, Akbar SM, Furukawa S, et al.Impaired functional capacities of liver dendritic cells from murine hepatitis B virus (HBV) carriers: relevance to low HBV-specific immune responses[J].Clin Exp Immunol.2005,139(1):35~42
[15] Tavakoli S, Schwerin W, Rohwer A,et al. Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection[J].J Gen Virol. 2004,85(Pt 10):2829~2836
[16] Van der Molen RG, Sprengers D, Binda RS, et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B[J].Hepatology.2004,40(3): 738~746
[17] Akbar SM, Horiike N, Onji M, et al.Dendritic cells and chronic hepatitis virus carriers[J]. Intervirology. 2001,44(4):199~208
[18] Zheng BJ, Zhou J, Qu D, et al. Selective functional deficit in dendritic cell-T cell interaction is a crucial mechanism in chronic hepatitis B virus infection[J]. J Viral Hepat. 2004, 11(3):217~224
[19] French AR,Yokoyama WM.Natural killer cells and viral infections[J].Current Opinion in Immunology.2003,15(1): 45~51
[20] Hamerman JA, Ogasawara K, Lanier LL.NK cells in innate immunity[J].Current Opinion in Immunology.2005,17(1):29~35
[21] Hakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection[J].Science. 2004,305(5685):872~874
[22] Chen Y, Wei H, Sun R, et al. Impaired function of hepatic natural killer cells from murine chronic HBsAg carriers[J].Int Immunopharmacol.2005,5(13-14): 1839~1852
[23] Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection[J].Science.2004,305(5685): 872~874
[24]李用国,梁增伟,蔡大川,等.树突状细胞体外激活的CTL杀伤效应[J].重庆医科大学学报.2003, 28: 138~139
[25]李用国,陈敏,张大志,等.自体树突状细胞疫苗治疗慢性乙型肝炎的临床研究[J].中华肝脏病杂志.2003,11:206~208
[26] Cools N, Van Tendeloo VF, Smits EL, et al. Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4(+) regulatory T cells[J].J Cell Mol Med.2008 ,12(2):690~700
[27] Li M, Zhang X, Zheng X, et al. Tolerogenic dendritic cells transferring hyporesponsiveness and synergizing T regulatory cells in transplant tolerance[J]. Int Immunol.2008,20(2):285~293
[28] Lau AW, Biester S, Cornall RJ,et al. Lipopolysaccharide-activated IL-10 secreting dendritic cells suppress experimental autoimmune uveoretinitis by MHCII-dependent activation of CD62L-expressing regulatory T cells[J].J Immunol.2008,180(6):3889~3899
[29] Sousa-Canavez JM, Canavez FC, Leite KR, et al.Therapeutic Dendritic cell vaccine preparation using tumor RNA transfection:A promise approach to treat prostate cance[J].Genet Vaccines Ther.2008,6:2
[30] Royer PJ, Bougras G, Ebstein F,et al.Efficient monocyte-derived dendritic cell generation in patients with acute myeloid leukemia after chemotherapy treatment: Application to active immunotherapy[J].Exp Hematol.2008, 36(3):329~339
[31] Apewalis C, Jacobs B, Wuttke M,et al.IFN-{alpha} Skews Monocytes into CD56+-Expressing Dendritic Cells with Potent Functional Activities In Vitro and In Vivo[J].J Immunol.2008,180(3): 1462~1470
[32] Xiong SQ, Lin BL, Gao X, et al. IL-12 promotes HBV-specific central memory CD8+T cell responses by PBMCs from chronic hepatitis B virus carriers[J]. Int Immunopharmacol.2007,7(5):578~587
[33] Eichler H, Nguyen XD, Roelen D, et al. Multicenter study on in vitro characterization of dendritic cells[J].Cytotherapy. 2008,10(1):21~29
[34] Castellano G, Woltman AM, Schlagwein N, et al. Immune modulation of humandendritic cells by complement[J].Eur J Immunol.2007,37(10):2803~2811
[35] Repnik U, Bergant M, Wraber B, et al. Late dendritic cells are still able to evoke a potent alloreactive CTL response[J].Immunobiology.2008,213(1):51~64
[36] Pepper M, Dzierszinski F, Wilson E, et al. Plasmacytoid Dendritic Cells Are Activated by Toxoplasma gondii to Present Antigen and Produce Cytokines[J].J Immunol.2008,180(9):6229~6236
[37] Frasca L, Nasso M, Spensieri F, et al. IFN-{gamma} Arms Human Dendritic Cells to Perform Multiple Effector Functions[J].J Immunol.2008,180(3): 1471~1481
[38] Saito K, Ait-Goughoulte M, Truscott SM, et al. Hepatitis C virus inhibits cell surface expression of HLA-DR, prevents dendritic cell maturation and induces IL-10 production[J]. J Virol.2008,82(7):3320~3328
[39] Theiner G, Rossner S, Dalpke A, et al.TLR9 cooperates with TLR4 to increase IL-12 release by murine dendritic cells[J].Mol Immunol,2008,45(1):244~252
[40] Lehner M, Morhart P, Stilper A,et al.Efficient chemokine-dependent migration and primary and secondary IL-12 secretion by human dendritic cells stimulated through Toll-like receptors[J].J Immunother.2007,30(3):312~322
[41] Qiu SJ, Lu L, Qiao C, et al. Induction of tumor immunity and cytotoxicT lymphocyte responses using dendritic cells transduced by adenoviral vectors encoding HBsAg: comparison to protein immunization[J].J Cancer Res Clin Oncol 2005,131(7):429~438
[42] H?nig J, Lutz MB. Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing[J].J Immunol.2008,180(3): 1405~1413
[43]中华医学会肝病学分会、感染病学分会.慢性乙型肝炎防治指南[J].中华肝脏病杂志.2005,13(12):881~891
[44]中华医学会传染病与寄生虫病学分会,中华医学会肝病学分会.病毒性肝炎防治方案[J].中华传染病学杂志.2001,19(1):56~62
[45] Conroy H, Marshall NA, Mills KH. TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours[J].Oncogene. 2008,27(2):168~180
[46] Cools N, Ponsaerts P, Van Tendeloo VF, et al.Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector Tcells[J].J Leukoc Biol.2007,82(6):1365~1374
[47] Matsuda Y, Toda M, Kato T, et al.Fulminant liver failure triggered by therapeutic antibody treatment in a mouse model[J].Int J Oncol.2006,29(5): 1119~1125
[1] Steinman RM, Cohn ZA.Pillars Article: Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution[J].J Exp Med.1973,137:1142~1162
[2] Usharauli D.Dendritic cells and the immunity/tolerance decision[J].Med Hypotheses. 2005,64(1):112~113
[3] Errington F, Steele L, Prestwich R, et al.Reovirus Activates Human Dendritic Cells to Promote Innate Antitumor Immunity[J].J Immunol.2008,180(9): 6018~6026
[4] Guermonprez P, Amigorena S.An export-reimport model for cross presentation of particulate antigens by MHC class I molecules in dentritic cells[J].J Soc Biol.2004,198(2):121~122
[5] Ponsaerts P, Van den Bosch G, Cools N, et al.Messenger RNA electroporation of human monocytes, followed by rapid in vitro differentiation, leads to highly stimulatory antigen-loaded mature dendritic cells[J].J Immunol.2002,169(4): 1669~1675
[6] Cuellar A, Fonseca A, Gomez A.Effect of lipopolysaccharides on human dendritic cell cultures and its inhibition by polymyxin B[J].Biomedica. 2004,24(4):413~422
[7] Den Brok MH, Nierkens S, Figdor CG, et al. Dendritic cells: tools and targets for antitumor vaccination[J].Expert Rev Vaccines.2005,4(5):699~710
[8] Tsiatas ML, Gritzapis AD, Cacoullos NT, et al.A novel culture environment for generating mature human dentritic cells from peripheral blood CD14+ cells[J].Anticancer Res. 2001,21(2A):1199~1206
[9] Pepper M, Dzierszinski F, Wilson E, et al.Plasmacytoid Dendritic Cells Are Activated by Toxoplasma gondii to Present Antigen and Produce Cytokines[J].J Immunol.2008,180(9): 6229~6236
[10] Caux C, Dezutter-Dambuyant C, Schmitt D, et al.GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells[J].Nature.1992, 360(6401):258~261
[11] Colonna M,Trinchieri G,Liu YJ.Plasmacytoid dendritic cells in immunity[J].Nat Immunol.2004,5(12):1219~1226
[12] Wilson NS,EL-Sukkari D,Villadangos JA.Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by ericontrolling the rates of MHC classⅡsynthesis and endocytosis[J]. Blood,2004,103(6):2187~2195
[13] Parslow TG,Stites DP,Terr AL,Imboden JB[M].Medical Immunology.10thed. New York:McGrawHill,2000
[14] Smits EL, Ponsaerts P, Van de Velde AL, et al. Proinflammatory response of humanleukemic cells to dsRNA transfection linked to activation of dendritic cells[J].Leukemia. 2007,21(8):1691~1699
[15] Lamhamedi-Cherradi SE, Martin RE, Ito T, et al.Fungal Proteases Induce Th2 Polarization through Limited Dendritic Cell Maturation and Reduced Production of IL-12[J].J Immunol. 2008,180(9):6000~6009.
[16]陈智超,李菁媛,姚军霞,等.DC-CIK细胞治疗自体外周血造血干细胞移植后急性髓性白血病的临床研究[J].临床内科杂志.2007,24(9)596~598
[17] Ni HT,Spelman SR,Jean WC,et a1.Immunization with dendritic ceils pulsed with tumor extract increases survival of mice bearing intracranial gliomas[J].J Neurooncol,2001,51(1):1~9
[18] Ehtesham M,Kabos P,Gutierrez MA,et a1.Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity against malignant glioma in rats[J].J Immunother.2003,6(2):107~116
[19] Yamanaka R,Abe T,Yajima N,et a1.Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic ceils elicits immune responses:results of a clinical phase I/II trial[J].Br J Cancer,2003,89(7):1172~1179
[20]张韬,周新荣,牛洪泉,等.对负载人胶质瘤冻融抗原的树突状细胞功能的实验研究[J].中国临床神经外科杂志.2003,8(4):242~244
[21]薛德麟,雷霆,董震,等.脑胶质瘤自体疫苗的临床实验研究[J].中华实验外科杂志.2003,20(2):139~l40
[22] Kono K,Takahashi A,Sugai H,et al.Dendritic cells pulsed with HER-2/neu -derived peptides can induce specific T-cell responses in patients with gastric cancer[J]. Clin Cancer Res. 2002 ,8(11):3394~400
[23] Liau LM,Black KL,Prins RM,et a1.Treatment of in.tracranial gliomas with bone marrow-derived dendritic cels pulsed with tumor antigens[J].J Neurosurg,1999,90(6):1115~1124
[24]刘福生,王忠诚,厉俊华,等.肿瘤抗原致敏树突状细胞瘤苗治疗颅内胶质瘤的实验研究[J].中华神经外科杂志.2002,18(2):91~95
[25] Yu JS,Wheeler CJ,Zehzer PM,et a1.Vaccination of malignant glioma patients withpeptide-pulsed dendritic cels elicits systemic cytotoxicity and intracranial T celinfiltration [J].Cancer Res.2001,61:842~847
[26] Ribas A, Butterfield LH, Hu B, et al. Generation of T-cell immunity to a murine melanoma using MART-1-engineered dendritic cells[J].J Immunother. 2000,23(1):59~66
[27] Pecher G, Schirrmann T, Kaiser L,et al.Efficient cryopreservation of dendritic cells transfected with cDNA of a tumour antigen for clinical application[J]. Biotechnol Appl Biochem.2001, 34 (Pt 3):161~162
[28] Pecher G, H?ring A, Kaiser L,et al.Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial[J].Cancer Immunol Immunother. 2002 ,51(11-12):669~673
[29] Pecher G, Spahn G, Schirrmann T, et al.Mucin gene (MUC1) transfer into human dendritic cells by cationic liposomes and recombinant adenovirus[J].Anticancer Res.2001, 21(4A):2591~2596
[30] Pecher G, Finn OJ.Induction of cellular immunity in chimpanzees to human tumor-associated antigen mucin by vaccination with MUC-1 cDNA-transfected Epstein-Barr virus-immortalized autologous B cells[J].Proc Natl Acad Sci USA. 1996, 93(4):1699~1704
[31] Mach N, Gillessen S, Wilson SB, et al.Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony- stimulating factor or Flt3- ligand[J].Cancer Res.2000,60(12): 3239~3246
[32] Ju DW,Tao Q,Lou G,et al.Interleukin 18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates[J].Cancer Res.2001, 61(9):3735~3740
[33] Wang Q, Yu H, Ju DW,et al.Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma[J].Gene Ther.2001,8(7):542~550
[34] Ju DW, Yang Y, Tao Q, et al.Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity [J].Gene Ther.2000,7(19):1672~1679
[35] Zheng BJ, Zhou J, Qu D,et al.Selective functional deficit in dendritic cell--T cell interaction is a crucial mechanism in chronic hepatitis B virus infection [J].J Viral Hepat.2004,11(3):217~224
[36] Tavakoli S, Mederacke I, Herzog-Hauff S, et al. Peripheral blood dendritic cells are phenotypically and functionally intact in chronic hepatitis B virus (HBV) infection[J].Clin Exp Immunol.2008,51(1):61~70
[37] Zhang Z, Chen D, Yao J,et al.Increased infiltration of intrahepatic DC subsets closely correlate with viral control and liver injury in immune active pediatric patients with chronic hepatitis B.Clin Immunol[J].2007,122(2):173~180
[38] Untergasser A, Zedler U, Langenkamp A,et al.Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection[J]. Hepatology.2006,43(3):539~547
[39] Chen M, Li YG, Zhang DZ,et al.Therapeutic effect of autologous dendritic cell vaccine on patients with chronic hepatitis B: a clinical study[J].World J Gastroenterol.2005,11(12):1806~1808
[40]黄呈辉,欧阳玲,黄建国,等.HBV抗原基因修饰树突状细胞疫苗体外抗HBV的作用.世界华人消化杂志.2006,14(19):1864~1869
[41] Qiu SJ, Lu L, Qiao C,et al.Induction of tumor immunity and cytotoxic t lymphocyte responses using dendritic cells transduced by adenoviral vectors encoding HBsAg: comparison to protein immunization[J].J Cancer Res Clin Oncol.2005,131(7):429~438
[42] Kim YS, Yang SH, Kang HG,et al. Distinctive role of donor strain immature dendritic cells in the creation of allograft tolerance[J].Int Immunol. 2006,18(12):1771~1777
[43] Cools N, Van Tendeloo VF, Smits EL, et al.Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4(+) regulatory T cells[J].J Cell Mol Med.2008,12(2):690~700
[44] Cools N, Ponsaerts P, Van Tendeloo VF, et al.Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector Tcells[J].J Leukoc Biol.2007,82(6):1365~1374
[45] Shah PD, Gilbertson SM, Rowley DA. Dendritic cells that have interacted with antigen are targets for natural killer cells[J].J Exp Med. 1985,162(2):625~636
[46] Fernandez NC, Lozier A, Flament C, et al.Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo[J].Nat Med,1999,5(4):405~411
[47] Chiesa MD, Sivori S, Castriconi R, et al. Pathogen-induced private conversations between natural killer and dendritic cells[J].Trends Microbiol. 2005,13(3):128~136
[48] Gerosa F, Gobbi A, Zorzi P, et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions[J].J Immunol,2005,174(2):727~734
[49] Andrews DM, Andoniou CE, Scalzo AA, et al.Cross-talk between dendritic cells and natural killer cells in viral infection[J].Mol Immunol,2005, 42(4):547~555
[50] Kalinski P, Giermasz A, Nakamura Y,et al. Helper role of NK cells during the induction of anticancer responses by dendritic cells[J].Mol Immunol.2005, 42(4):535~539
[51] Piccioli D, Sbrana S, Melandri E,et al.Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells[J].J Exp Med.2002,195(3): 335~341