肝细胞癌AFPmRNA转染CD40配体活化的B细胞诱导抗肿瘤免疫的实验研究
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摘要
目的
①本研究拟构建AFP真核表达载体,体外转染CD40L活化的B淋巴细胞,制备AFP-B细胞瘤苗。诱导针对AFP特异性CTL免疫作用。初步探讨肿瘤非特异性抗原AFP作为靶点用于肝癌免疫治疗的可行性。
②利用肝癌细胞株Hepal-6总RNA转染CD40L活化的小鼠B细胞,探讨其诱导特异性细胞毒性T淋巴细胞(CTL)抗肿瘤免疫作用。
方法
①利用密度梯度离心法从小鼠脾脏淋巴细胞悬液分离、纯化T、B淋巴细胞,并在CD40L和rmIL-4联合作用下活化B细胞。并利用流式细胞仪分析B淋巴细胞表面标志及主要组织相容性抗原的表达情况。
②利用RT-PCR克隆出目的基因AFPcDNA,定向插入pGEM4Z/A64质粒,从而制备成pGEM4Z/AFP/A64质粒。并经酶切,电泳鉴定。利用SpeI限制性内切酶使pGEM4Z/AFP/A64质粒进行线性化,在T7RNA聚合酶作用下,体外转录出AFPmRNA。
③随后将AFPmRNA转染入CD40L活化的B细胞,观察转染前后B细胞的表型变化。同时将转染的B淋巴细胞刺激T淋巴细胞诱导、扩增CTL,检测CTL杀伤活性及分泌IFN-γ的水平。
④提取肝癌细胞Hepal-6总RNA,然后转染活化B细胞,检测转染后各组B细胞表面APC标记及主要组织相容性抗原的表达情况。转染的B淋巴细胞刺激T淋巴细胞,诱导、扩增CTL,检测CTL杀伤活性及分泌IFN-γ的水平。
结果
①CD40L和rmIL-4活化的B细胞表面分子CD40、CD86、CD80、H-2Kb及I-Ab表达流式检测阳性细胞数明显高于对照组,两组相比较p<0.05。活化的B细胞刺激T细胞的所测得光密度值高于对照组,两者比较p<0.05。
②成功构建AFP真核表达载体,酶切、电泳鉴定可见一清晰条带位于1800bp左右,与目的基因1818bp相符。利用Western blot方法可检测出有70kD左右的特异性蛋白条带,与目的基因蛋白分子量70kD相符。
③转染AFPmRNA的B细胞表面组织相容性分子及共刺激分子分别高于未转染组,两者比较(P<0.01)。转染活化的B细胞刺激T细胞增殖能力高于未转染组(P<0.01)。转染的B细胞诱导的特异性杀伤率高于未转染组,两者比较(P<0.01)。转染的B细胞刺激的T细胞产生的CTL分泌INF-γ的水平高于对照组(P<0.01)。
④提取的Hepal-6总RNA经琼脂糖凝胶电泳显示有28S、18S和5S三条带。转染总RNA的B细胞其表面组织相容性分子及共刺激分子表达高于小鼠肝细胞RNA组,两者相比较p<0.05；也明显高于脂质体对照组及空白对照组,与其相比较p<0.01。转染的B淋巴细胞刺激T细胞所测OD值高于对照组,与其比较有统计学意义。转染的B淋巴细胞诱导的特异性杀伤率高于对照组,两组比较(p<0.05)。转染的B细胞刺激产生CTL分泌INF-γ的水平显著高于对照组,两组相比较p<0.05。
结论
①AFPmRNA转染活化的B淋巴细胞在体外能诱导产生针对AFP特异性CTL反应。
②以肝癌细胞Hepal-6总RNA转染的B淋巴细胞,也可有效诱导CTL杀伤肝癌细胞。为肝癌治疗提供了两种可能的新思路。
Objectives
First, to construct AFP eukaryotic expression vector, then transcribe AFPmRNA and transfect it into B lymphocytes activated by CD40L in vitro for preparation of AFP-B cell vaccine. And induce specific CTL immunity against AFP.then discuss preliminary the feasibility of immunotherapy of hepatocellular carcinoma as a target for AFP.
Second, Total RNA of Hepal-6,a hepatocelluar carcinoma cell line,were introduced into mouse B lymphocytes activated by CD40L,then study the antitumor effectivity of B lymphocytes in the context of inducing cytotoxic T lymphocytes (CTLs).
Methods
First, T and B lymphocytes were collected, isolated and purfied from mouse spleen lymphocytes by density gradient centrifugation method. B cells were initially activated by CD40L and rmIL-4. The expression of B cell markers and major histocomability complex (MHC) on cell surface were detected by FCM.
Second, the goal gene AFPcDNA was cloned by RT-PCR. Insert cloned AFPcDNA into the plasmid pGEM4Z/A64 in the direction to create the plasmid pGEM4Z/AFP/A64. It was determined by enzyme digestion and electrophoretic analysis. Linearization of pGEM4Z/AFP/A64 with SpeI, then followed by in vitro transcription AFPmRNA with T7 RNA polymerase.
Third, AFPmRNA was transfected into activated B lymphocytes. The expression of B cell surface markers was determined.CTL was obtained by stimulating T lymphocytes with transfected B lymphocytesd, and then the killing activity of CTL and the IFN-r secretion were quantified.
Last, Total RNA was extracted from Hepal-6, and then it was transfected into B lymphocytes. The expressions of antigen presenting cell markers and major histocomability complex on cell surface were detected, and then the killing activity of CTL and the IFN-r secretion were quantified.
Results
First, The MHC and co-stimulating molecules(CD40,CD86,CD80,H-2Kb,I-Ab) expression of B lymphocytes activated by CD40L and rmIL-4 were higher than unactivated B cells(p<0.05). OD value of B cell activated stimulator T cell was higher than unactivated B cell group (p<0.05).
Second, the vector pGEM4Z/AFP/A64 was constructed, and it was determined by enzyme digestion and electrophoretic analysis that a clear band at 1800bp position was showed, consistenting with the target gene 1818bp. A 70.0kD specific protein band was detected by Western blot; consistenting with molecular weight of the target protein.
Third, the MHC and co-stimulating molecules expression of B lymphocytes transfected by AFPmRNA were higher than untransfected B cells, comparison between the two groups (p<0.01). OD value of transfected B cell stimulator T cell was higher than untransfected B cell group(p<0.05).The killing activity and IFN-y secretion of CTL after stimulation of AFPmRNA-transfected B lymphocyte was more significant than control group, comparison between the two groups (p<0.01).
Last, Electrophoresis of the whole RNA extracted from Hepal-6 cells showed that 28s,18s and 5s bands. The MHC and co-stimulating molecules expression increased significantly higher than other groups after total RNA transfected, comparison with the concrol groups p<0.05. OD value of B lymphocyte transfected by total RNA stimulator T cell was higher than control groups.The killing activity and IFN-y secretion of CTL after stimulation of RNA-transfected B lymphocyte was more significant than control group (p<0.05).
Conclusion
First, B lymphocytes loaded with AFPmRNA can induce AFP-specific CTL in vitro.
Second, HCC RNA-transfected B lymphocyte is capable of inducing anti-tumor effects through CTL response. It may present two potential pathways for future HCC treatment.
①本研究拟构建AFP真核表达载体,体外转染CD40L活化的B淋巴细胞,制备AFP-B细胞瘤苗。诱导针对AFP特异性CTL免疫作用。初步探讨肿瘤非特异性抗原AFP作为靶点用于肝癌免疫治疗的可行性。
②利用肝癌细胞株Hepal-6总RNA转染CD40L活化的小鼠B细胞,探讨其诱导特异性细胞毒性T淋巴细胞(CTL)抗肿瘤免疫作用。
方法
①利用密度梯度离心法从小鼠脾脏淋巴细胞悬液分离、纯化T、B淋巴细胞,并在CD40L和rmIL-4联合作用下活化B细胞。并利用流式细胞仪分析B淋巴细胞表面标志及主要组织相容性抗原的表达情况。
②利用RT-PCR克隆出目的基因AFPcDNA,定向插入pGEM4Z/A64质粒,从而制备成pGEM4Z/AFP/A64质粒。并经酶切,电泳鉴定。利用SpeI限制性内切酶使pGEM4Z/AFP/A64质粒进行线性化,在T7RNA聚合酶作用下,体外转录出AFPmRNA。
③随后将AFPmRNA转染入CD40L活化的B细胞,观察转染前后B细胞的表型变化。同时将转染的B淋巴细胞刺激T淋巴细胞诱导、扩增CTL,检测CTL杀伤活性及分泌IFN-γ的水平。
④提取肝癌细胞Hepal-6总RNA,然后转染活化B细胞,检测转染后各组B细胞表面APC标记及主要组织相容性抗原的表达情况。转染的B淋巴细胞刺激T淋巴细胞,诱导、扩增CTL,检测CTL杀伤活性及分泌IFN-γ的水平。
结果
①CD40L和rmIL-4活化的B细胞表面分子CD40、CD86、CD80、H-2Kb及I-Ab表达流式检测阳性细胞数明显高于对照组,两组相比较p<0.05。活化的B细胞刺激T细胞的所测得光密度值高于对照组,两者比较p<0.05。
②成功构建AFP真核表达载体,酶切、电泳鉴定可见一清晰条带位于1800bp左右,与目的基因1818bp相符。利用Western blot方法可检测出有70kD左右的特异性蛋白条带,与目的基因蛋白分子量70kD相符。
③转染AFPmRNA的B细胞表面组织相容性分子及共刺激分子分别高于未转染组,两者比较(P<0.01)。转染活化的B细胞刺激T细胞增殖能力高于未转染组(P<0.01)。转染的B细胞诱导的特异性杀伤率高于未转染组,两者比较(P<0.01)。转染的B细胞刺激的T细胞产生的CTL分泌INF-γ的水平高于对照组(P<0.01)。
④提取的Hepal-6总RNA经琼脂糖凝胶电泳显示有28S、18S和5S三条带。转染总RNA的B细胞其表面组织相容性分子及共刺激分子表达高于小鼠肝细胞RNA组,两者相比较p<0.05；也明显高于脂质体对照组及空白对照组,与其相比较p<0.01。转染的B淋巴细胞刺激T细胞所测OD值高于对照组,与其比较有统计学意义。转染的B淋巴细胞诱导的特异性杀伤率高于对照组,两组比较(p<0.05)。转染的B细胞刺激产生CTL分泌INF-γ的水平显著高于对照组,两组相比较p<0.05。
结论
①AFPmRNA转染活化的B淋巴细胞在体外能诱导产生针对AFP特异性CTL反应。
②以肝癌细胞Hepal-6总RNA转染的B淋巴细胞,也可有效诱导CTL杀伤肝癌细胞。为肝癌治疗提供了两种可能的新思路。
Objectives
First, to construct AFP eukaryotic expression vector, then transcribe AFPmRNA and transfect it into B lymphocytes activated by CD40L in vitro for preparation of AFP-B cell vaccine. And induce specific CTL immunity against AFP.then discuss preliminary the feasibility of immunotherapy of hepatocellular carcinoma as a target for AFP.
Second, Total RNA of Hepal-6,a hepatocelluar carcinoma cell line,were introduced into mouse B lymphocytes activated by CD40L,then study the antitumor effectivity of B lymphocytes in the context of inducing cytotoxic T lymphocytes (CTLs).
Methods
First, T and B lymphocytes were collected, isolated and purfied from mouse spleen lymphocytes by density gradient centrifugation method. B cells were initially activated by CD40L and rmIL-4. The expression of B cell markers and major histocomability complex (MHC) on cell surface were detected by FCM.
Second, the goal gene AFPcDNA was cloned by RT-PCR. Insert cloned AFPcDNA into the plasmid pGEM4Z/A64 in the direction to create the plasmid pGEM4Z/AFP/A64. It was determined by enzyme digestion and electrophoretic analysis. Linearization of pGEM4Z/AFP/A64 with SpeI, then followed by in vitro transcription AFPmRNA with T7 RNA polymerase.
Third, AFPmRNA was transfected into activated B lymphocytes. The expression of B cell surface markers was determined.CTL was obtained by stimulating T lymphocytes with transfected B lymphocytesd, and then the killing activity of CTL and the IFN-r secretion were quantified.
Last, Total RNA was extracted from Hepal-6, and then it was transfected into B lymphocytes. The expressions of antigen presenting cell markers and major histocomability complex on cell surface were detected, and then the killing activity of CTL and the IFN-r secretion were quantified.
Results
First, The MHC and co-stimulating molecules(CD40,CD86,CD80,H-2Kb,I-Ab) expression of B lymphocytes activated by CD40L and rmIL-4 were higher than unactivated B cells(p<0.05). OD value of B cell activated stimulator T cell was higher than unactivated B cell group (p<0.05).
Second, the vector pGEM4Z/AFP/A64 was constructed, and it was determined by enzyme digestion and electrophoretic analysis that a clear band at 1800bp position was showed, consistenting with the target gene 1818bp. A 70.0kD specific protein band was detected by Western blot; consistenting with molecular weight of the target protein.
Third, the MHC and co-stimulating molecules expression of B lymphocytes transfected by AFPmRNA were higher than untransfected B cells, comparison between the two groups (p<0.01). OD value of transfected B cell stimulator T cell was higher than untransfected B cell group(p<0.05).The killing activity and IFN-y secretion of CTL after stimulation of AFPmRNA-transfected B lymphocyte was more significant than control group, comparison between the two groups (p<0.01).
Last, Electrophoresis of the whole RNA extracted from Hepal-6 cells showed that 28s,18s and 5s bands. The MHC and co-stimulating molecules expression increased significantly higher than other groups after total RNA transfected, comparison with the concrol groups p<0.05. OD value of B lymphocyte transfected by total RNA stimulator T cell was higher than control groups.The killing activity and IFN-y secretion of CTL after stimulation of RNA-transfected B lymphocyte was more significant than control group (p<0.05).
Conclusion
First, B lymphocytes loaded with AFPmRNA can induce AFP-specific CTL in vitro.
Second, HCC RNA-transfected B lymphocyte is capable of inducing anti-tumor effects through CTL response. It may present two potential pathways for future HCC treatment.
引文
1. Schultze JL, Grabbe S, von Berqwelt-Baildon MS.DCs and CD40-activated B cells:current and future avenues to cellular cancer immunotherapy.Trends [J] Immunol,2004,25(12):659～664.
2. Svane IM,Soot ML,Buus S,et al.Clinical application of dendritic cells in cancer vaccination therapy[J].APMIS,2003,111 (7-8):818-834.
3. Mu LJ, Gaudernack G, Saeboe-Larssen S, et al.Protocol for generation of clinical grade Mrna-transfected monocyte-derived dendritic cells for cancer vaccines [J].Scand J Immunol,2003,58(5):578-586.
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1. Yamashita T, Nakane A, Watanabe T, et al. Evidence that alpha-fetoprotein suppresses the immunological function in transgenic mice [J]. Biochem Biophys Res Commun,1994,201(3):1154-1159.
2. Vollmer CM, Eilber FC, Butterfield LH, et al.Alpha-fetoprotein specific genetic immunotherapy for hepatocellular carcinoma[J]. Cancer Res,1999, 59(13):3064-3067.
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5. Butterfield LH, Koh A, Meng WS, et al.Generation of human T cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein [J].Cancer Res,1999,59(13):3134-3142.
6. Meng WS, Butterfield LH, Ribas A, et al. Alpha-fetoprotein specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination [J]. Cancer Res,2001,61(24):8782-8786.
7. Grimm CF, Ortmann D, Mohr L, et al.Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice[J].Gastroenterology,2000,119(4):1104-1112.
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1. EI-Seraq HB, Rudolph KL.Hepatocellular carcinoma:epidemiology and molecular carcinogenesis [J].Gastroenterology,2007,132(7):2557-2576.
2. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002[J].Cancer J Clin, 2005,55(2):74-108.
3. Schultze JL, Grabbe S, von Berqwelt-Baildon MS.DCs and CD40-activated B cells:current and future avenues to cellular cancer immunotherapy.Trends [J] Immunol,2004,25(12):659～664.
4. Svane IM,Soot ML,Buus S,et al.Clinical application of dendritic cells in cancer vaccination therapy[J].APMIS,2003,111 (7-8):818-834.
5. Mu LJ, Gaudernack G, Saeboe-Larssen S, et al. A protocol for generation of clinical grade Mrna-transfected monocyte-derived dendritic cells for cancer vaccines [J].Scand J Immunol,2003,58(5):578-586.
6. Schultze JL, Michalak S, Seamon MJ, et al. CD40-activated human B cells:an alternative source of highly effcient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy [J].J Clin Invest, 1997,100(11):2757-2765.
7. Lapointe R,Lapointe R,Bellemare-Pelletier A,et al.CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells[J]. Cancer Res,2003,63(11):2836-2843.
8. Saenz Badillos J, Amin SP and Granstein RD.RNA as a tumor vacine:a review of the literature [J].Exp Dermatol,2001,10(3):143-154.
9. Grunebach F,Muller MR,Nencioni A,et al.Delivery of tumor-derived RNA for the induction of cytotoxic T-lymphocytes [J].Gene Therapy,2003(5),10:367-374.
10. Heiser A,Maurice MA,Yancey DR,et al.Human dendritic cells transfected with renal tumor RNA stimulate polyclonal Tcell responses against antigens expressed by primaryand metastatic tumors[J].Cancer Res,2001,61(8):3388-3393.
11. Heiser A, Maurice MA, Yancey DR, et al. Induction of polyclonal prostate cancer-specific CTL using dendritic cells transfected with amplified tumor RNA [J]J Immunol,2001,166(5):2953-2960.
12. Boczkowski D, Nair SK, Nam JH, et al. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells [J].Cancer Res,2000,60(4):1028-1034.
13.Kariko K, Kuo A, Barnathan ES, et al. Phosphate-enhanced transfection of cationic lipid-complexed mRNA and plasmid DNA[J].Biochim Biophys Acta,1998, 369(2):320-334.
14. Yamashita T, Nakane A, Watanabe T, et al. Evidence that alpha-fetoprotein suppresses the immunological function in transgenic mice [J]. Biochem Biophys Res Commun,1994,201(3):1154-1159.
15. Vollmer CM, Eilber FC, Butterfield LH, et al.Alpha-fetoprotein specific genetic immunotherapy for hepatocellular carcinoma[J]. Cancer Res,1999, 59(13):3064-3067.
16. Butterfield LH, Ribas A, Meng WS, et al. T-Cell Responses to HLA-A*0201 Immunodominant Peptides Derived from alpha-fetoprotein in Patients with Hepatocellular Cancer [J]. Clinical Cancer Research,2003,9(1):5902-5908
17. Hanke P, Rabe C, Serwe M, et al.Cirrhotic patients with or without hepatocellular carcinoma harbour AFP-specific T-lymphocytes that can be activated in vitro by human alpha-fetoprotein [J].Scand J Gastroenterol,2002,37(8):949-955.
18. Butterfield LH, Koh A, Meng WS, et al.Generation of human T cell responses to an HL A-A2.1-restricted peptide epitope derived from alpha-fetoprotein [J].Cancer Res,1999,59(13):3134-3142.
19. Meng WS, Butterfield LH, Ribas A, et al. Alpha-fetoprotein specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination [J]. Cancer Res,2001,61(24):8782-8786.
20. Grimm CF, Ortmann D, Mohr L, et al.Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice[J].Gastroenterology,2000,119(4):1104-1112.
21. Xue Gang,Cheng Ying,Cao Yongkuan,et al. The effect of INF-γ gene modified dendritic cells on T cell proliferation and eradication of tumor cells[J]. Chinese Journal of General Surgery,2008,17(4):340-345.
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4. EI-Seraq HB, Rudolph KL.Hepatocellular carcinoma:epidemiology and molecular carcinogenesis [J].Gastroenterology,2007,132(7):2557-2576.
5. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002[J].Cancer J Clin, 2005,55(2):74-108.
6. Schultze JL, Grabbe S, von Berqwelt-Baildon MS.DCs and CD40-activated B cells:current and future avenues to cellular cancer immunotherapy.Trends [J] Immunol,2004,25(12):659～664.
7. Svane IM,Soot ML,Buus S,et al.Clinical application of dendritic cells in cancer vaccination therapy[J].APMIS,2003,111 (7-8):818-834.
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