Suppression of hepatocarcinogenesis by activating natural killer T cells
通过激活自然杀伤 T 细胞抑制肝癌发生
基本信息
- 批准号:14570468
- 负责人:
- 金额:$ 2.18万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2003
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Innate immune response serves as a first line of defense against carcinogenesis. Since lives contain lots of innate immune effector cells, such as NKT cells and NK cells, innate immune response may be especially important to elicit anti-tumor immunity in the liver. In the present study, we investigated anti-tumor effect elicited by administration of αGalCer or innate cytokine genes against liver tumors in mice. Administration of αGalCer, a ligand for Va14 NKT cell receptor, completely suppressed the growth of BNL hepatoma cells disseminated in the liver of syngeneic mice. αGalCer administration rapidly activated hepatic NKT cells followed by a prolonged activation of NK cells. In vivo depletion of NK cells by anti-asialo GM1 antibody completely abrogated the therapeutic effect. Injection of naked plasmid DNA encoding either IFNα gene or pIL-12 gene, but not mock plasmid, efficiently activated hepatic NK cells for 1 week and completely eradicated hepatic metastasis of CT-26 colon tumor cells. The rejection is dependent on the presence of NK cells, since in vivo depletion of NK cells by injecting asialoGM1 antibody abolished the anti-tumor activity of both gene therapies. The mice that had been protected from hepatic tumor by both therapies were challenged with subcutaneous inoculation of original tumor cells. αGalCer-or pIL-12-injected mice completely rejected re-challenged tumor cells, and pIFNa-injected mice did partially. The present study revealed that injection of αGalCer and innate cytokine genes such as IL-12 and IFNα protect from hepatic metastasis in a NKT cell or NK cell dependent manner. Furthermore, tumor rejection provoked by activation of innate immune cells efficiently induced acquired immune response against original tumor cells.
先天免疫反应是抵抗癌症发生的第一道防线。由于生命中含有大量的天然免疫效应细胞,如NKT细胞和NK细胞,因此天然免疫应答对于在肝脏中引发抗肿瘤免疫可能特别重要。在本研究中,我们研究了αGalCer或先天性细胞因子基因对小鼠肝肿瘤的抗肿瘤作用。给予Va 14 NKT细胞受体的配体αGalCer可完全抑制同系小鼠肝脏中播散的BNL肝癌细胞的生长。αGalCer给药快速激活肝脏NKT细胞,随后延长NK细胞的激活。通过抗脱唾液酸基GM 1抗体体内耗竭NK细胞完全消除了治疗效果。注射编码IFNα基因或pIL-12基因的裸质粒DNA(而不是模拟质粒)可有效激活肝脏NK细胞1周,并完全根除CT-26结肠肿瘤细胞的肝转移。排斥反应依赖于NK细胞的存在,因为通过注射脱唾液酸GM 1抗体体内消耗NK细胞消除了两种基因疗法的抗肿瘤活性。通过皮下接种原始肿瘤细胞来攻击通过两种疗法保护免于肝肿瘤的小鼠。注射α GalCer或pIL-12的小鼠完全排斥再激发的肿瘤细胞,而注射pIFNa的小鼠部分排斥。目前的研究表明,注射αGalCer和先天性细胞因子基因如IL-12和IFNα以NKT细胞或NK细胞依赖的方式保护肝转移。此外,由先天免疫细胞激活引起的肿瘤排斥有效地诱导针对原始肿瘤细胞的获得性免疫应答。
项目成果
期刊论文数量(33)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Jinushi, M., et al.: "Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid"Int.J.Cancer. 104. 354-361 (2003)
Jinushi, M., 等人:“MICA 和 MICB 在人肝细胞癌中的表达和作用及其受视黄酸的调节”Int.J.Cancer。
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- 发表时间:
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- 影响因子:0
- 作者:
- 通讯作者:
Jinushi M, Takehara T, et al.: "Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection."Journal of Immunology. 171(10). 5423-5429 (2003)
Jinushi M、Takehara T 等人:“I 型 IFN 介导的 MHC I 类相关链 A 和 B 的树突状细胞表达所需的自分泌/旁分泌 IL-15 在丙型肝炎病毒感染中受损。”
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- 发表时间:
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- 影响因子:0
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Miyagi T, et al.: "Impaired expression of proteasome subunits and human leukocyte antigens class I in human colon cancer cells"J Gastroenterol Hepatol. 18. 32-40 (2003)
Miyagi T 等人:“人类结肠癌细胞中蛋白酶体亚基和人类白细胞抗原 I 类的表达受损”J Gastroenterol Hepatol。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
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- 通讯作者:
Jinushi M, Takehara T, et al.: "Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid."International Journal of Cancer. 104(3). 354-361 (2003)
Jinushi M、Takehara T 等人:“MICA 和 MICB 在人肝细胞癌中的表达和作用及其受视黄酸的调节。”国际癌症杂志。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, Suzuki T, Miyagi T, Hayashi N.: "Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus
Jinushi M、Takehara T、Tatsumi T、Kanto T、Groh V、Spies T、Suzuki T、Miyagi T、Hayashi N.:“I 型 IFN 介导的 MHC 类树突状细胞表达所需的自分泌/旁分泌 IL-15
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- 影响因子:0
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TAKEHARA Tetsuo其他文献
TAKEHARA Tetsuo的其他文献
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{{ truncateString('TAKEHARA Tetsuo', 18)}}的其他基金
Molecular mechanisms of acinar cell injury in acute pancreatitis
急性胰腺炎腺泡细胞损伤的分子机制
- 批准号:
24659364 - 财政年份:2012
- 资助金额:
$ 2.18万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Regulation of autophagy and its impact in the development and progression of hepatocellular cancer.
自噬的调节及其对肝细胞癌发生和进展的影响。
- 批准号:
23390197 - 财政年份:2011
- 资助金额:
$ 2.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Bcl-2 network and regulation of cell death in non-alcoholic steatohepatitis
Bcl-2网络与非酒精性脂肪性肝炎细胞死亡的调节
- 批准号:
21659188 - 财政年份:2009
- 资助金额:
$ 2.18万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Molecular mechanism of the ectodomain shedding of the NKG2D ligand MHC class I-related chain A in hepatocellular carcinoma and its therapeutic implication
肝癌中NKG2D配体MHC I类相关链A胞外域脱落的分子机制及其治疗意义
- 批准号:
20390208 - 财政年份:2008
- 资助金额:
$ 2.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Molecular regulation of NK cell cytotoxicity fir human hepatocellular carcinoma
NK细胞对人肝细胞癌细胞毒性的分子调控
- 批准号:
18390216 - 财政年份:2006
- 资助金额:
$ 2.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Natural killer receptor-mediated regulation of dendritic cell functions in chronic hepatitis C
自然杀伤受体介导的慢性丙型肝炎树突状细胞功能的调节
- 批准号:
16390207 - 财政年份:2004
- 资助金额:
$ 2.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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