IL-15基因联合肿瘤抗原修饰树突状细胞抗前列腺癌的实验研究
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摘要
目的:
1.构建携带mouseIL-15基因的复制缺陷型腺病毒载体(Ad-GFP-mIL-15)并大量制备。
2.建立从小鼠骨髓前体细胞中分离、培养和扩增树突状细胞(dendritic cell,DC)的方法;将Ad-GFP-mIL-15和RM-1小鼠前列腺癌细胞裂解产物上清(Lysate)共同修饰DC,构建新型前列腺癌DC疫苗(IL-15/lysate-DC),评价其免疫生物学特性。
3.通过体外、体内实验证实IL-15/lysate-DC疫苗抗前列腺癌免疫治疗作用,为以DC为基础的前列腺癌免疫治疗和基因转染治疗提供新的策略。
方法:
1.以小鼠肾脏cDNA为模板,用pfx DNA ploymerase扩增mIL-15目的基因,扩增得到的目的基因片段克隆到pGEM-T Easy Vector上,得到mIL-15-T克隆载体;从mIL-15-T克隆载体上EcoRI双酶切得到mIL-15基因,连接到pShuttle-GFP-CMV载体上,得到pShuttle-GFP-mIL-15;将pShuttle-GFP-mIL-15转移到pAdxsi载体上,得到Ad-GFP-mIL-15病毒质粒,并完成了腺病毒的大量扩增和纯化。
2.从小鼠骨髓分离DC前体细胞,在细胞因子GM-CSF和IL-4联合作用下,大量制备骨髓源性DC(bone marrow derived DC,BM-DC)。采用形态学(光镜)、免疫细胞化学和免疫生物学等方法研究DC的免疫生物学特性。将Ad-GFP-mIL-15病毒转染联合RM-1小鼠前列腺癌细胞的裂解产物上清(Lysate)共同修饰DC,制备IL-15/lysate-DC前列腺癌疫苗。
3.体外实验检测IL-15/lysate-DC刺激同基因型T细胞增殖能力、刺激T淋巴细胞亚群表型分析,刺激同基因型小鼠T细胞增殖反应中淋巴细胞培养上清IFN-γ、IL-10水平,诱导CTL能力及杀伤活性。
4.建立RM-1前列腺癌细胞荷瘤小鼠动物模型,观察IL-15/lysate-DC疫苗对荷瘤小鼠的免疫治疗作用,并分析其可能的作用机制;ELISA方法检测荷瘤小鼠治疗后血清中IFN-γ和IL-10表达水平。
结果:
1.所构建的Ad-GFP-mIL-15病毒质粒,经酶切电泳、测序及RT-PCR鉴定,证实重组腺病毒载体构建正确,插入片段包含mIL-15基因序列。
2.在细胞因子GM-CSF和IL-4诱导下,体外培养5天后,可从每只小鼠骨髓DC前体细胞中获得5～10×106个DC。早期未成熟DC表达很低的表面共刺激分子、黏附分子和MHC分子,刺激T细胞增殖能力极弱;5天的DC在转染Ad-GFP-mIL-15 48小时后,表面共刺激分子、黏附分子和MHC分子明显上调,混合淋巴细胞反应(mixed lymphocyte reaction,MLR)强烈;将Ad-GFP-mIL-15联合RM-1小鼠前列腺癌细胞的裂解产物上清(Lysate)共同修饰DC,制备IL-15/lysate-DC前列腺癌疫苗,流式细胞仪(flow cytometry,FCM)检测其表面共刺激分子、黏附分子和MHC分子明显上调。
3. IL-15/lysate-DC前列腺癌疫苗刺激同基因型小鼠脾脏T淋巴细胞增殖能力明显升高;刺激同基因型小鼠脾脏T淋巴细胞亚群表型分析,证实IL-15/lysate-DC可使T淋巴细胞中CD8+T亚群比例细胞明显升高;刺激同基因型小鼠T细胞增殖反应中淋巴细胞培养上清IFN-γ、IL-10的检测,证实IL-15/lysate-DC组淋巴细胞上清中IFN-γ水平明显增高,IL-10水平最低;在诱导CTL能力及杀伤活性检测实验中,四氮唑蓝(methyl thiazolyl tetrazolium ,MTT)还原法显示IL-15/lysate-DC组对RM-1前列腺癌细胞的特异性细胞杀伤率最高;上述实验中,IL-15/lysate-DC组与GFP/lysate-DC组、Lysate-DC组相比,差异有显著性意义(P<0.05)。
4. RM-1细胞前列腺癌荷瘤小鼠模型构建成功,成瘤率100%。IL-15/lysate-DC治疗组荷瘤生长减缓,生存期延长。接种RM-1前列腺癌细胞10周后,IL-15/lysate-DC组仍有50%的小鼠存活,上述实验中,IL-15/lysate-DC组与GFP/lysate-DC组、Lysate-DC组、PBS组相比,差异有显著性意义(P<0.05)。
5. ELISA检测显示,荷瘤小鼠经免疫治疗2次后,IL-15/lysate-DC组血清IFN-γ水平明显增高,IL-10水平最低,与GFP/lysate-DC组、Lysate-DC组、PBS组相比,差异有显著性意义(P<0.05);组织学检查发现,IL-15/lysate-DC治疗组的荷瘤鼠,瘤体内、瘤周有大量炎性细胞(淋巴、单核细胞)浸润,肿瘤组织局部坏死明显。GFP/lysate-DC组、Lysate-DC组也可见瘤体内部分组织坏死及炎性细胞浸润,但明显少于IL-15/lysate-DC组,PBS组几乎无肿瘤坏死及炎性细胞浸润。
结论:
1.成功构建了Ad-GFP-mIL-15病毒质粒。
2.在细胞因子GM-CSF和IL-4诱导下,可从小鼠骨髓前体细胞中获得足够数量DC;转染Ad-GFP-mIL-15能促进DC成熟、上调MHC-Ⅱ类分子、表面共刺激分子和黏附分子的表达,MLR检测示刺激T细胞增殖能力明显提高。
3.IL-15/lysate-DC疫苗能激发同基因型T淋巴细胞增殖,诱导IFN-γ因子分泌能力强,使T淋巴细胞中CD8+T细胞亚群比例明显升高;所诱导的特异性CTL对RM-1前列腺癌细胞有显著的杀伤作用。
4.观察IL-15/lysate-DC疫苗治疗荷瘤小鼠,发现有明显的抗肿瘤作用,能减缓肿瘤生长速度,使荷瘤小鼠生存期延长;治疗后血清IFN-γ水平明显增高,肿瘤组织出现明显坏死和淋巴细胞浸润,能诱导强烈的全身和局部肿瘤免疫应答。
Objective:
To construct the replication-deficient adenovirus vector encoding mouse IL-15 gene (Ad-GFP-mIL-15) and prepare a lot. To establish the methods of isolation, purification and propagation of mouse bone marrow-derived dendritic cells(DC), investigate the changes of morphological structure and bio-immunological characteristics of DC during its development, differentiation and maturation, study the related factors involved in proliferation and polarization of DC. To construct the DC vaccine modified with mouse IL-15 gene and cell lysate on mice with prostate cancer. To detect and analyze the specific antitumor activity and immunotherapeutic effect of DC vaccine(IL-15/lysate-DC)both in vitro and in vivo.
Methods:
Mouse kidney cDNA as a template, by using pfx DNA ploymerase amplified mIL-15 gene. Amplified target gene fragment was cloned into pGEM-T Easy Vector. mIL-15 gene recevied from the mIL-15-T cloning vector EcoRI digestion and connected to the pShuttle-GFP-CMV vector.Ad-GFP-mIL-15 virus plasmid was received by pShuttle-GFP-mIL-15 transfer to pAdxsi vector. The correct adenovirus plasmid was substantially amplified and purified. The mouse bone marrow progenitors were isolated andcultured with cytokines of mrGM-CSF plus mrIL-4, and a large amount of BM-DC were harvested after selection and culture for 5 or 7days. The bio-immunological features and functions of DC in different stages were studied by using methods of light- microscopy, mixed leucocyte reaction(MLR), flow cytometry(FCM), and so on. Mouse bone marrow DC were transfected with the recombinant adenovirus vector encoding mIL-15 gene and pulsed with cell lysate from RM-1 mouse prostate cancer cell line. The ability of stimulating syngeneic T cells, T-lymphocyte subsets analysis, IFN-γ, IL-10 level of lymphocyte culture supernatant and the effect of inducing specific kill activity of IL-15/lysate-DC vaccine were detected. The immunotherapeutic effect IL-15/lysate-DC vaccine and IFN-γ, IL-10 level of serum on mice with prostate cancer was assessed.
Results:
1.By digestion, electrophoresis, sequencing and RT-PCR identification, we successfully constructed the recombinant adenovirus vector encoding mIL-15 gene.
2.About 5～10×106 DC were havested from bone marrow progenitors per mouse followed culturing the cells with rmGM-CSF plus rmIL-4 for 5 days. In early stage, DC expressed very low level of costimulatory molecules, adhesion molecules and MHC molecules and failed to stimulate allogeneic T cell proliferation. Cultured DC transfected with Ad-GFP-IL-15 on 5 days, they expressed very high level of costimulatory molecules, adhesion molecules and MHC molecules and stronger activity of stimulating T cell proliferation on 7 days. IL-15/lysate-DC vaccine was contructed by transfected with the recombinant adenovirus vector encoding mIL-15 gene and pulsed with cell lysate from RM-1 mouse prostate cancer cell line.
3.The ability of stimulating T cells proliferation, CD8+T cells proportion in T-lymphocyte subsets and IFN-γlevel of lymphocyte culture supernatant were significantly increased by IL-15/lysate-DC stimulating with the allogeneic of mouse spleen T lymphocyte proliferation reaction. The mice immunized with DC pulsed with RM-1 cell lysate (Lysate-DC) exhibited a specific CTL response, but the highest CTL activity against RM-1 cells was induced by immunization with IL-15/lysate-DC(P<0.05).
4.In the mice model with pre-established subcutaneous RM-1 prostate cancer cell, vaccination with Lysate-DC and GFP/lysate-DC vaccine could inhibit tumor growth, but the immunization of IL-15/lysate-DC vaccine inhibit the tumor growth most significantly when compared with Lysate-DC and GFP/lysate-DC(P < 0.05). The survival time of the mice treated with IL-15/lysate-DC Vaccine was also greatly extended(P<0.05).
5.Histological examination showed that the most obvious tumor necrosis and infiltration of inflammatory cells was present inside and around the tumor of the tumor-bearing mice immunized with IL-15/lysate-DC Vaccine when compared with Lysate-DC and GFP/lysate-DC(P<0.05). Immunotherapy of tumor-bearing mice with IL-15/lysate-DC vaccine could increase the the production of IFN-γby serum test when compared with Lysate-DC and GFP/lysate-DC(P<0.05).
Couclusions:
1.The recombinant adenovirus vector encoding mIL-15 gene was constructed successfully.
2. A sufficient number of functional DC were havested from bone marrow progenitors mouse followed culturing the cells with rmGM-CSF plus rmIL-4. After DC were transfected with Ad-GFP-IL-15, they expressed very high level of costimulatory molecules, adhesion molecules and MHC molecules and stronger activity of stimulating T cell proliferation.
3.The ability of stimulating T cells proliferationand and IFN-γlevel of lymphocyte culture supernatant were significantly increased by IL-15/lysate-DC stimulating with the allogeneic of mouse spleen T lymphocyte proliferation reaction. The highest CTL activity against RM-1 cells was induced by immunization with IL-15/lysate-DC.
4.IL-15/lysate-DC might elicit significant antitumor effects through efficient induction of systemic and local immune responses against prostate cancer.
1.构建携带mouseIL-15基因的复制缺陷型腺病毒载体(Ad-GFP-mIL-15)并大量制备。
2.建立从小鼠骨髓前体细胞中分离、培养和扩增树突状细胞(dendritic cell,DC)的方法;将Ad-GFP-mIL-15和RM-1小鼠前列腺癌细胞裂解产物上清(Lysate)共同修饰DC,构建新型前列腺癌DC疫苗(IL-15/lysate-DC),评价其免疫生物学特性。
3.通过体外、体内实验证实IL-15/lysate-DC疫苗抗前列腺癌免疫治疗作用,为以DC为基础的前列腺癌免疫治疗和基因转染治疗提供新的策略。
方法:
1.以小鼠肾脏cDNA为模板,用pfx DNA ploymerase扩增mIL-15目的基因,扩增得到的目的基因片段克隆到pGEM-T Easy Vector上,得到mIL-15-T克隆载体;从mIL-15-T克隆载体上EcoRI双酶切得到mIL-15基因,连接到pShuttle-GFP-CMV载体上,得到pShuttle-GFP-mIL-15;将pShuttle-GFP-mIL-15转移到pAdxsi载体上,得到Ad-GFP-mIL-15病毒质粒,并完成了腺病毒的大量扩增和纯化。
2.从小鼠骨髓分离DC前体细胞,在细胞因子GM-CSF和IL-4联合作用下,大量制备骨髓源性DC(bone marrow derived DC,BM-DC)。采用形态学(光镜)、免疫细胞化学和免疫生物学等方法研究DC的免疫生物学特性。将Ad-GFP-mIL-15病毒转染联合RM-1小鼠前列腺癌细胞的裂解产物上清(Lysate)共同修饰DC,制备IL-15/lysate-DC前列腺癌疫苗。
3.体外实验检测IL-15/lysate-DC刺激同基因型T细胞增殖能力、刺激T淋巴细胞亚群表型分析,刺激同基因型小鼠T细胞增殖反应中淋巴细胞培养上清IFN-γ、IL-10水平,诱导CTL能力及杀伤活性。
4.建立RM-1前列腺癌细胞荷瘤小鼠动物模型,观察IL-15/lysate-DC疫苗对荷瘤小鼠的免疫治疗作用,并分析其可能的作用机制;ELISA方法检测荷瘤小鼠治疗后血清中IFN-γ和IL-10表达水平。
结果:
1.所构建的Ad-GFP-mIL-15病毒质粒,经酶切电泳、测序及RT-PCR鉴定,证实重组腺病毒载体构建正确,插入片段包含mIL-15基因序列。
2.在细胞因子GM-CSF和IL-4诱导下,体外培养5天后,可从每只小鼠骨髓DC前体细胞中获得5～10×106个DC。早期未成熟DC表达很低的表面共刺激分子、黏附分子和MHC分子,刺激T细胞增殖能力极弱;5天的DC在转染Ad-GFP-mIL-15 48小时后,表面共刺激分子、黏附分子和MHC分子明显上调,混合淋巴细胞反应(mixed lymphocyte reaction,MLR)强烈;将Ad-GFP-mIL-15联合RM-1小鼠前列腺癌细胞的裂解产物上清(Lysate)共同修饰DC,制备IL-15/lysate-DC前列腺癌疫苗,流式细胞仪(flow cytometry,FCM)检测其表面共刺激分子、黏附分子和MHC分子明显上调。
3. IL-15/lysate-DC前列腺癌疫苗刺激同基因型小鼠脾脏T淋巴细胞增殖能力明显升高;刺激同基因型小鼠脾脏T淋巴细胞亚群表型分析,证实IL-15/lysate-DC可使T淋巴细胞中CD8+T亚群比例细胞明显升高;刺激同基因型小鼠T细胞增殖反应中淋巴细胞培养上清IFN-γ、IL-10的检测,证实IL-15/lysate-DC组淋巴细胞上清中IFN-γ水平明显增高,IL-10水平最低;在诱导CTL能力及杀伤活性检测实验中,四氮唑蓝(methyl thiazolyl tetrazolium ,MTT)还原法显示IL-15/lysate-DC组对RM-1前列腺癌细胞的特异性细胞杀伤率最高;上述实验中,IL-15/lysate-DC组与GFP/lysate-DC组、Lysate-DC组相比,差异有显著性意义(P<0.05)。
4. RM-1细胞前列腺癌荷瘤小鼠模型构建成功,成瘤率100%。IL-15/lysate-DC治疗组荷瘤生长减缓,生存期延长。接种RM-1前列腺癌细胞10周后,IL-15/lysate-DC组仍有50%的小鼠存活,上述实验中,IL-15/lysate-DC组与GFP/lysate-DC组、Lysate-DC组、PBS组相比,差异有显著性意义(P<0.05)。
5. ELISA检测显示,荷瘤小鼠经免疫治疗2次后,IL-15/lysate-DC组血清IFN-γ水平明显增高,IL-10水平最低,与GFP/lysate-DC组、Lysate-DC组、PBS组相比,差异有显著性意义(P<0.05);组织学检查发现,IL-15/lysate-DC治疗组的荷瘤鼠,瘤体内、瘤周有大量炎性细胞(淋巴、单核细胞)浸润,肿瘤组织局部坏死明显。GFP/lysate-DC组、Lysate-DC组也可见瘤体内部分组织坏死及炎性细胞浸润,但明显少于IL-15/lysate-DC组,PBS组几乎无肿瘤坏死及炎性细胞浸润。
结论:
1.成功构建了Ad-GFP-mIL-15病毒质粒。
2.在细胞因子GM-CSF和IL-4诱导下,可从小鼠骨髓前体细胞中获得足够数量DC;转染Ad-GFP-mIL-15能促进DC成熟、上调MHC-Ⅱ类分子、表面共刺激分子和黏附分子的表达,MLR检测示刺激T细胞增殖能力明显提高。
3.IL-15/lysate-DC疫苗能激发同基因型T淋巴细胞增殖,诱导IFN-γ因子分泌能力强,使T淋巴细胞中CD8+T细胞亚群比例明显升高;所诱导的特异性CTL对RM-1前列腺癌细胞有显著的杀伤作用。
4.观察IL-15/lysate-DC疫苗治疗荷瘤小鼠,发现有明显的抗肿瘤作用,能减缓肿瘤生长速度,使荷瘤小鼠生存期延长;治疗后血清IFN-γ水平明显增高,肿瘤组织出现明显坏死和淋巴细胞浸润,能诱导强烈的全身和局部肿瘤免疫应答。
Objective:
To construct the replication-deficient adenovirus vector encoding mouse IL-15 gene (Ad-GFP-mIL-15) and prepare a lot. To establish the methods of isolation, purification and propagation of mouse bone marrow-derived dendritic cells(DC), investigate the changes of morphological structure and bio-immunological characteristics of DC during its development, differentiation and maturation, study the related factors involved in proliferation and polarization of DC. To construct the DC vaccine modified with mouse IL-15 gene and cell lysate on mice with prostate cancer. To detect and analyze the specific antitumor activity and immunotherapeutic effect of DC vaccine(IL-15/lysate-DC)both in vitro and in vivo.
Methods:
Mouse kidney cDNA as a template, by using pfx DNA ploymerase amplified mIL-15 gene. Amplified target gene fragment was cloned into pGEM-T Easy Vector. mIL-15 gene recevied from the mIL-15-T cloning vector EcoRI digestion and connected to the pShuttle-GFP-CMV vector.Ad-GFP-mIL-15 virus plasmid was received by pShuttle-GFP-mIL-15 transfer to pAdxsi vector. The correct adenovirus plasmid was substantially amplified and purified. The mouse bone marrow progenitors were isolated andcultured with cytokines of mrGM-CSF plus mrIL-4, and a large amount of BM-DC were harvested after selection and culture for 5 or 7days. The bio-immunological features and functions of DC in different stages were studied by using methods of light- microscopy, mixed leucocyte reaction(MLR), flow cytometry(FCM), and so on. Mouse bone marrow DC were transfected with the recombinant adenovirus vector encoding mIL-15 gene and pulsed with cell lysate from RM-1 mouse prostate cancer cell line. The ability of stimulating syngeneic T cells, T-lymphocyte subsets analysis, IFN-γ, IL-10 level of lymphocyte culture supernatant and the effect of inducing specific kill activity of IL-15/lysate-DC vaccine were detected. The immunotherapeutic effect IL-15/lysate-DC vaccine and IFN-γ, IL-10 level of serum on mice with prostate cancer was assessed.
Results:
1.By digestion, electrophoresis, sequencing and RT-PCR identification, we successfully constructed the recombinant adenovirus vector encoding mIL-15 gene.
2.About 5～10×106 DC were havested from bone marrow progenitors per mouse followed culturing the cells with rmGM-CSF plus rmIL-4 for 5 days. In early stage, DC expressed very low level of costimulatory molecules, adhesion molecules and MHC molecules and failed to stimulate allogeneic T cell proliferation. Cultured DC transfected with Ad-GFP-IL-15 on 5 days, they expressed very high level of costimulatory molecules, adhesion molecules and MHC molecules and stronger activity of stimulating T cell proliferation on 7 days. IL-15/lysate-DC vaccine was contructed by transfected with the recombinant adenovirus vector encoding mIL-15 gene and pulsed with cell lysate from RM-1 mouse prostate cancer cell line.
3.The ability of stimulating T cells proliferation, CD8+T cells proportion in T-lymphocyte subsets and IFN-γlevel of lymphocyte culture supernatant were significantly increased by IL-15/lysate-DC stimulating with the allogeneic of mouse spleen T lymphocyte proliferation reaction. The mice immunized with DC pulsed with RM-1 cell lysate (Lysate-DC) exhibited a specific CTL response, but the highest CTL activity against RM-1 cells was induced by immunization with IL-15/lysate-DC(P<0.05).
4.In the mice model with pre-established subcutaneous RM-1 prostate cancer cell, vaccination with Lysate-DC and GFP/lysate-DC vaccine could inhibit tumor growth, but the immunization of IL-15/lysate-DC vaccine inhibit the tumor growth most significantly when compared with Lysate-DC and GFP/lysate-DC(P < 0.05). The survival time of the mice treated with IL-15/lysate-DC Vaccine was also greatly extended(P<0.05).
5.Histological examination showed that the most obvious tumor necrosis and infiltration of inflammatory cells was present inside and around the tumor of the tumor-bearing mice immunized with IL-15/lysate-DC Vaccine when compared with Lysate-DC and GFP/lysate-DC(P<0.05). Immunotherapy of tumor-bearing mice with IL-15/lysate-DC vaccine could increase the the production of IFN-γby serum test when compared with Lysate-DC and GFP/lysate-DC(P<0.05).
Couclusions:
1.The recombinant adenovirus vector encoding mIL-15 gene was constructed successfully.
2. A sufficient number of functional DC were havested from bone marrow progenitors mouse followed culturing the cells with rmGM-CSF plus rmIL-4. After DC were transfected with Ad-GFP-IL-15, they expressed very high level of costimulatory molecules, adhesion molecules and MHC molecules and stronger activity of stimulating T cell proliferation.
3.The ability of stimulating T cells proliferationand and IFN-γlevel of lymphocyte culture supernatant were significantly increased by IL-15/lysate-DC stimulating with the allogeneic of mouse spleen T lymphocyte proliferation reaction. The highest CTL activity against RM-1 cells was induced by immunization with IL-15/lysate-DC.
4.IL-15/lysate-DC might elicit significant antitumor effects through efficient induction of systemic and local immune responses against prostate cancer.
引文
1.Fong L, Engleman EG. Dendritic cells in cancer immunotherapy[J]. Annu Rev Immunol, 2000, 18: 245-273.
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