Analysis of CTL targeted on hepatoma transfected with HIV gene Innovation of vaccine against hepatitis C virus.

HIV基因转染肝癌靶向CTL分析丙型肝炎病毒疫苗创新

• 批准号: 14570473
• 负责人: KUROKOHCHI Kazutaka
• 金额: $ 2.11万
• 依托单位: Kagawa University(Faculty of Medicine)
• 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: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570473/
• 关键词: Hepatitis C; Hepatitis C virus; Cytotoxic T lymphocytes; Immunology; Costimulatory molecule; Hepatocellular carcinoma; Radiofrequency ablation (RFA); 制御性T細胞; T細胞受容体(TCR)

The pathogenic mechanism for hepatocellular damage in HCV infection has not been clearly understood. Peripheral blood mononuclear cells (PBMCs) and liver infiltrating mononuclear cells (LIMCs) isolated from the HCV-infected patients were analyzed with antibodies directed against a variety of co-stimulatory molecules by flow cytometry. PBMCs expressing CD8,CD28,CD80 or CD154 were significantly reduced in HCV-infected patients compared with the healthy controls. CD28(+)CD8(+)PBMCs in the patients inversely correlated with ALT levels. Conversely, levels of CD28(-)CD8(+)LIMCs correlated with ALT levels. HCV-specific CTL activity was blocked by the treatment with anti-CB8 antibody, but not with anti-CD4 or anti-CD28 antibody. Immunohistochemical analysis revealed the accumulation of CD28(+) cells around the portal area in the liver of a patient with chronic active hepatitis C. These results suggest that CD28(+)CD8(+) T cells leave the circulation, move to the livers and are activated in the portal area in proportion to the extent of liver diseases. CD28(-)CD8(+) T cells may finally function as effector T cells causing the hepatocellular damage in HCV infection.Radiofrequency ablation (RFA) is currently used for the treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the usefullness of combination therapy of percutaneous ethanol injection (PEI) and RFA (PEI-RFA). Patients with biopsy-proven HCC and liver cirrhosis underwent RFA after a bolus injection of ethanol into HCC (PEI-RFA). The volume of coagulated necrosis was estimated and compared with that in the group treated with RFA alone. Significantly larger coagulated necrosis areas were observed in patients treated with PEI-RFA compared with those treated with RFA alone. In the PEI-RFA group, the volume of coagulated necrosis was significantly correlated with the amounts of ethanol injected into HCC. No major complications were observed during and after the PEIRFA treatment.

HCV感染引起肝细胞损伤的致病机制尚不清楚。通过流式细胞术用针对各种共刺激分子的抗体分析从HCV感染患者分离的外周血单核细胞（PBMC）和肝浸润单核细胞（LMCs）。与健康对照组相比，HCV感染患者PBMC表达CD 8、CD 28、CD 80或CD 154的水平显著降低。CD 28（+）CD 8（+）PBMC与ALT水平呈负相关。相反，CD 28（-）CD 8（+）LMCs水平与ALT水平相关。HCV特异性CTL活性可被抗CB 8抗体阻断，但不能被抗CD 4或抗CD 28抗体阻断。免疫组织化学分析显示，慢性活动性丙型肝炎患者肝脏汇管区周围有CD 28（+）细胞聚集。这些结果表明，CD 28（+）CD 8（+）T细胞离开循环，移动到肝脏，并在汇管区激活，与肝脏疾病的程度成比例。HCV感染时，CD 28（-）CD 8（+）T细胞可能最终发挥效应T细胞的作用，导致肝细胞损伤。本研究的目的是评价经皮无水乙醇注射（PEI）和射频消融（PEI-RFA）联合治疗的有效性。经活检证实的HCC和肝硬化患者在向HCC中团注乙醇后接受RFA（PEI-RFA）。估计凝固性坏死的体积，并与单独RFA治疗组进行比较。与仅接受RFA治疗的患者相比，在接受PEI-RFA治疗的患者中观察到明显更大的凝固性坏死区域。在PEI-RFA组中，凝固性坏死的体积与注入HCC的乙醇量显著相关。PEIRFA治疗期间和治疗后未观察到重大并发症。

项目成果

Kurokohchi K, Masaki T, Arima K, 8 Others.: "CD28-negative CD8-positive cytotoxic T lymphocytes mediate Hepatocellular damage in hepatitis C virus infection."J Clin Immunol. 23. 518-527 (2003)

Kurokohchi K、Masaki T、Arima K、8 其他人：“CD28 阴性 CD8 阳性细胞毒性 T 淋巴细胞介导丙型肝炎病毒感染中的肝细胞损伤。”J Clin Nutrition。

Kuriyama S, Yoshiji H, Masaki T, 12 Others(2^<nd>): "ARCHMEDIA (Tokyo) Induction of hepatoma specific gene expression using the chimera regulatory factor including AFP promoter."Arcmedium Tokyo. 93-99 (2003)

Kuriyama S、Yoshiji H、Masaki T、12 其他（2^<nd>）：“ARCHMEDIA（东京）使用包括 AFP 启动子的嵌合调节因子诱导肝癌特异性基因表达。”Arcmedium 东京。

Watanabe S, Sasahara K, Kinekawa F, 8 Others (6th): "Aldehyde dehydrogenase-2 genotypes and HLA haplotypes in Japanese patients with esophageal cancer"Oncol Rep. 9. 1063-1068 (2002)

Watanabe S、Sasahara K、Kinekawa F、8 其他（第 6 篇）：“日本食道癌患者中的醛脱氢酶 2 基因型和 HLA 单倍型”Oncol Rep. 9. 1063-1068 (2002)

黒河内和貴, 栗山茂樹: "抗結核剤リファンピシンのチトクロームP450に与える影響"消化器科. 35. 655-659 (2002)

Kazuki Kurokochi、Shigeki Kuriyama：“抗结核药物利福平对细胞色素 P450 的影响”胃肠病学 35. 655-659 (2002)。

栗山茂樹, 吉治仁志, 正木勉ほか12名(5番目): "AFP遺伝子の制御領域を含むキメラ制御因子を用いた肝癌細胞選択的遺伝子発現の誘導.In:臨床応用を目指した消化器分子生物学(小俣政男 編)"アークメディア、東京. 93-99 (2003)

Shigeki Kuriyama、Hitoshi Yoshiji、Tsutomu Masaki 等 12 人（第 5 名）：“使用包含 AFP 基因调控区域的嵌合调控元件诱导肝癌细胞中的选择性基因表达。In：针对临床应用的胃肠道分子生物学研究（由 Masao Omata 编辑）”Arcmedia，东京 93-99 (2003)。