SLC联合IL-2转染DC对膀胱癌的研究
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摘要
目的:研究从人脐带血中分离的树突状细胞(dendritic cell,DC),在体外培养扩增后用次级淋巴细胞趋化因子(secondary lymphoid tissue chemokine,SLC)联合白细胞介素-2(interleukin-2,IL-2)进行基因转染DC,观察DC体外增殖能力变化以及与淋巴细胞培养能否增强对膀胱癌细胞的对正常膀胱平滑肌细胞的体外杀伤活性。
方法:用RT-PCR技术由人总RNA中克隆出SLC,将本实验室保存的质粒pBudCE4.1-SLC-IL-2酶切,切下SLC,电泳后回收另一个片段pBudCE4.1-IL-2,将SLC用相同的酶切后,与pBudCE4.1-IL-2连接,经PCR、限制性内切酶酶切确认酶切位点的有效性,测序确认基因序列的正确性。用分子生物学技术构建出pBudCE4.1-IL-2,pBudCE4.1-SLC,pBudCE4.1-SLC-IL-2三种重组质粒并予以鉴定。用细胞培养技术,从10例分娩的婴儿脐带血一般分离出DC。另一半培养成淋巴细胞,分别在体外进行扩增和培养,初步测定单纯在体外培养的DC与淋巴细胞培养后对正常膀胱平滑肌细胞和膀胱癌细胞系的杀伤效应。用电转染的方法,将空载体pBudCE4.1和三种重组载体真核表达载体pBudCE4.1-IL-2,pBudCE4.1-SLC,pBudCE4.1-SLC-IL-2转染到DC中,通过抗性标志筛选出抗Zeocin克隆,分别命名为DC/IL-2,DC/SLC,DC/SLC+IL-2和DC/vector,未转染DC命名为DC/Parental。应用Western blot分析转染前后以及转染不同载体后SLC和IL-2基因在DC中的表达。应用ELISA分析方法测定各组DC细胞IL-2的分泌量。将经过筛选、鉴定的DC与淋巴细胞作为效应细胞(effector cell,EC),正常膀胱平滑肌细胞和人膀胱癌细胞株细胞作为靶细胞(target cell,TC),固定EC:TC比例为20:1,用~(51)Cr释放实验测定DC与淋巴细胞混合物细胞毒活性。用流式细胞仪测定靶细胞凋亡率。
结果:成功克隆SLC和IL-2基因,并成功克隆到克隆载体和真核表达载体上。成功分离并体外培养了10例脐带血DC和淋巴细胞。将重组载体和空载体分别转染DC细胞并分离出抗性克隆。Western blot分析表明,转染相应载体后的DC分别表现出SLC、IL-2的增强表达。ELISA表明,DC/Parental,DC/IL-2 andDC/SLC+IL-2细胞克隆IL-2分泌量分别为19.82±2.48,511.10±52.36,和549.05±62.02 ng/10~6 cells/24h。转染IL-2基因后,DC能够在无外源IL-2刺激情况下依靠自我分泌IL-2而增殖。DC/Parental,DC/SLC and DC/SLC+IL-2细胞克隆SLC分泌量分别为29.82±4.43,506.10±42.36和567.34±52.05ng/10~6 cells/24h,在EC:TC比例为40:1的条件下,DC/Parental,DC/IL-2,DC/SLC和DC/SLC+IL-2对膀胱癌细胞的细胞毒活性21.2%±4.8%,32.1%±5.5%.63.5%±6.6%, and 78.1%±9.63%。而对正常膀胱平滑肌细胞则分别为8.29±1.6%,10.68±3.0%,7.28±2.6%,11.38±3.2%。流式细胞仪测定靶细胞凋亡率表明,DC/SLC and DC/SLC+IL-2作用于肿瘤细胞后,肿瘤细胞凋亡率明显增加。而且自体肿瘤细胞明显比细胞系细胞更加敏感。对照研究表明,DC/Parental和DC/vector比较,各项测量值均无明显差异。
结论:DC能够通过转染IL-2基因的方式获得自我刺激增殖的能力。转染SLC能够使DC增强其对肿瘤细胞的细胞毒活性,这种增强效应是由SLC所介导的。未经基因转染和转染后的DC都表现出对自体肿瘤细胞具有更强的细胞毒活性。表明自体肿瘤细胞具有更强的被DC杀伤的敏感性。转染SLC基因后,DC细胞诱导肿瘤细胞凋亡的能力明显增强。
Objectives. To investigate whether dentritic cells (DC) transfected with secondary lymphoid tissue chemokine(SLC) and interleukin-2 (IL-2) genes is capable of improving the potency and efficiency of propagation and cytotoxicity against bladder tumor cells in vitro.
Methods. SLC and IL-2 gene primer was designed basing on the corresponding gene sequence in GenBank. KpnⅠsite was introduced into the upstream of the primer and XhoⅠsite into downstream. The SLC gene was amplified with the template ofpET32a(+)-SLC (The plasmid is given by Biochemistry and MolecularBiology Laboratory of Third Military Medical University) .then SLC was cloned into pBudCE4.1-IL-2 vector(SLC was removed from pBudCE4.1- SLC-IL-2) to construct recombinant plasmid pBudCE4.1- SLC- IL-2 (The plasmid ispreserved in our Laboratory) . DCs were derived from 10 patients withNormal birth cord blood,Dendritic cell (DC) were transfected with pBudCE4.1/SLC- IL-2 by gene electric transfection.Protein expression was determined by Western blot and enzyme-linked immunosorbent assay. Cytotoxicity of T lymphocyte(TC) and DC_against the human bladder tumor cell were examined by chromium release assay(EC:TC=20:1). Flow cytometric analyses were performed to determine the apoptosis of tumor cells and the percentage of Treg.
Results. Results. A high level of expression of the human SLC and IL-2 stable transfected DC was observed. The mean IL-2 production was 19.82±2.48, 511.10 ±52.36, and 549.05±62.02 ng/10~6 cells/24 hours in the DC/parental, DC/IL-2, and DC/SLC+IL-2 genes, respectively. The mean SLC production was 29.82±4.43, 506.10±42.36, and 567.34±52.05 ng/10~6 cells/24 hours in the DC/parental, DC/SLC, and DC/SLC+IL-2 genes, respectively The mean cytotoxicity (effector/target ratio 40:1) of CTL/parental, CTL/IL-2, CTL/SLC, and CTL/SLC+IL-2 against human bladder rumor cell lines in the percentage of cytolysis was 21.2%±4.8%, 32.1%±5.5%, 63.5%±6.6%, and 78.1%±9.63%, respectively.
Conclusions. DC/SLC+IL-2 and DC/SLC were expanded by autocrine IL-2 and SLC. DC/SLC+IL-2 and DC/SLC showed significant cytotoxicity that was induced by SLC.IL-2 and CTLs,and demonstrated a potent cytotoxicity against bladder tumor cell lines
方法:用RT-PCR技术由人总RNA中克隆出SLC,将本实验室保存的质粒pBudCE4.1-SLC-IL-2酶切,切下SLC,电泳后回收另一个片段pBudCE4.1-IL-2,将SLC用相同的酶切后,与pBudCE4.1-IL-2连接,经PCR、限制性内切酶酶切确认酶切位点的有效性,测序确认基因序列的正确性。用分子生物学技术构建出pBudCE4.1-IL-2,pBudCE4.1-SLC,pBudCE4.1-SLC-IL-2三种重组质粒并予以鉴定。用细胞培养技术,从10例分娩的婴儿脐带血一般分离出DC。另一半培养成淋巴细胞,分别在体外进行扩增和培养,初步测定单纯在体外培养的DC与淋巴细胞培养后对正常膀胱平滑肌细胞和膀胱癌细胞系的杀伤效应。用电转染的方法,将空载体pBudCE4.1和三种重组载体真核表达载体pBudCE4.1-IL-2,pBudCE4.1-SLC,pBudCE4.1-SLC-IL-2转染到DC中,通过抗性标志筛选出抗Zeocin克隆,分别命名为DC/IL-2,DC/SLC,DC/SLC+IL-2和DC/vector,未转染DC命名为DC/Parental。应用Western blot分析转染前后以及转染不同载体后SLC和IL-2基因在DC中的表达。应用ELISA分析方法测定各组DC细胞IL-2的分泌量。将经过筛选、鉴定的DC与淋巴细胞作为效应细胞(effector cell,EC),正常膀胱平滑肌细胞和人膀胱癌细胞株细胞作为靶细胞(target cell,TC),固定EC:TC比例为20:1,用~(51)Cr释放实验测定DC与淋巴细胞混合物细胞毒活性。用流式细胞仪测定靶细胞凋亡率。
结果:成功克隆SLC和IL-2基因,并成功克隆到克隆载体和真核表达载体上。成功分离并体外培养了10例脐带血DC和淋巴细胞。将重组载体和空载体分别转染DC细胞并分离出抗性克隆。Western blot分析表明,转染相应载体后的DC分别表现出SLC、IL-2的增强表达。ELISA表明,DC/Parental,DC/IL-2 andDC/SLC+IL-2细胞克隆IL-2分泌量分别为19.82±2.48,511.10±52.36,和549.05±62.02 ng/10~6 cells/24h。转染IL-2基因后,DC能够在无外源IL-2刺激情况下依靠自我分泌IL-2而增殖。DC/Parental,DC/SLC and DC/SLC+IL-2细胞克隆SLC分泌量分别为29.82±4.43,506.10±42.36和567.34±52.05ng/10~6 cells/24h,在EC:TC比例为40:1的条件下,DC/Parental,DC/IL-2,DC/SLC和DC/SLC+IL-2对膀胱癌细胞的细胞毒活性21.2%±4.8%,32.1%±5.5%.63.5%±6.6%, and 78.1%±9.63%。而对正常膀胱平滑肌细胞则分别为8.29±1.6%,10.68±3.0%,7.28±2.6%,11.38±3.2%。流式细胞仪测定靶细胞凋亡率表明,DC/SLC and DC/SLC+IL-2作用于肿瘤细胞后,肿瘤细胞凋亡率明显增加。而且自体肿瘤细胞明显比细胞系细胞更加敏感。对照研究表明,DC/Parental和DC/vector比较,各项测量值均无明显差异。
结论:DC能够通过转染IL-2基因的方式获得自我刺激增殖的能力。转染SLC能够使DC增强其对肿瘤细胞的细胞毒活性,这种增强效应是由SLC所介导的。未经基因转染和转染后的DC都表现出对自体肿瘤细胞具有更强的细胞毒活性。表明自体肿瘤细胞具有更强的被DC杀伤的敏感性。转染SLC基因后,DC细胞诱导肿瘤细胞凋亡的能力明显增强。
Objectives. To investigate whether dentritic cells (DC) transfected with secondary lymphoid tissue chemokine(SLC) and interleukin-2 (IL-2) genes is capable of improving the potency and efficiency of propagation and cytotoxicity against bladder tumor cells in vitro.
Methods. SLC and IL-2 gene primer was designed basing on the corresponding gene sequence in GenBank. KpnⅠsite was introduced into the upstream of the primer and XhoⅠsite into downstream. The SLC gene was amplified with the template ofpET32a(+)-SLC (The plasmid is given by Biochemistry and MolecularBiology Laboratory of Third Military Medical University) .then SLC was cloned into pBudCE4.1-IL-2 vector(SLC was removed from pBudCE4.1- SLC-IL-2) to construct recombinant plasmid pBudCE4.1- SLC- IL-2 (The plasmid ispreserved in our Laboratory) . DCs were derived from 10 patients withNormal birth cord blood,Dendritic cell (DC) were transfected with pBudCE4.1/SLC- IL-2 by gene electric transfection.Protein expression was determined by Western blot and enzyme-linked immunosorbent assay. Cytotoxicity of T lymphocyte(TC) and DC_against the human bladder tumor cell were examined by chromium release assay(EC:TC=20:1). Flow cytometric analyses were performed to determine the apoptosis of tumor cells and the percentage of Treg.
Results. Results. A high level of expression of the human SLC and IL-2 stable transfected DC was observed. The mean IL-2 production was 19.82±2.48, 511.10 ±52.36, and 549.05±62.02 ng/10~6 cells/24 hours in the DC/parental, DC/IL-2, and DC/SLC+IL-2 genes, respectively. The mean SLC production was 29.82±4.43, 506.10±42.36, and 567.34±52.05 ng/10~6 cells/24 hours in the DC/parental, DC/SLC, and DC/SLC+IL-2 genes, respectively The mean cytotoxicity (effector/target ratio 40:1) of CTL/parental, CTL/IL-2, CTL/SLC, and CTL/SLC+IL-2 against human bladder rumor cell lines in the percentage of cytolysis was 21.2%±4.8%, 32.1%±5.5%, 63.5%±6.6%, and 78.1%±9.63%, respectively.
Conclusions. DC/SLC+IL-2 and DC/SLC were expanded by autocrine IL-2 and SLC. DC/SLC+IL-2 and DC/SLC showed significant cytotoxicity that was induced by SLC.IL-2 and CTLs,and demonstrated a potent cytotoxicity against bladder tumor cell lines
引文
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3、参与撰写标书:
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