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
• 负责人: TAKEHARA Tetsuo
• 金额: $ 7.58万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390216/
• 关键词: MICA; NKG2D; HCC; NK receptor; Liver; Tumor; Innate immunity; MICB; TAE; 自然免; MICB; Soluble MICA; Soluble MICB

Soluble forms of MHC class I-related chain A and B (MICA/B) increase in sera of patients with malignancy and impair the anti-tumor immune response by downregulating expression of their cognate immunoreceptor NKG2D. Recently, soluble MICA/B were reported to appear even in some premalignant diseases, raising the question about the impact of soluble MICA/B produced from tumors on the expression of NKG2D. The present study examined soluble MICA/B in chronic liver disease and hepatocellular carcinoma (HCC) and their involvement in the immune cell expression of NKG2D during transcatheter arterial embolization (TAE) for HCC. The levels of soluble MICA/B were significantly higher in chronic liver disease and HCC patients than in healthy volunteers. The progression of liver disease and that of the tumor were independent determinants for soluble MICA/B levels. Immunohistochemistry revealed that MICA/B was expressed not only in HCC tissue but also on hepatocytes in cirrhotic livers. The TAE therapy significantly decreased serum levels of soluble MICA, but not soluble MICB, and increased the NKG2D expression on NK cells and CD8-positive T cells; there was an inverse correlation between changes in soluble MICA levels and in NKG2D expression. In vitro experiments confirmed that MICA-containing sera clearly downregulated NKG2D expression and suppressed NKG2D-mediated effector cell function. In conclusion, although soluble MICA/B are produced from both HCC and premalignant cirrhotic livers, therapeutic intervention for HCC can reduce the levels of soluble MICA and thereby upregulate the expression of NKG2D. Cancer therapy may have a beneficial effect on the NKG2D-mediated anti-tumor immunity.

MHC i类相关链A和B （MICA/B）的可溶性形式在恶性肿瘤患者的血清中增加，并通过下调其同源免疫受体NKG2D的表达而损害抗肿瘤免疫反应。最近，有报道称可溶性MICA/B甚至出现在一些癌前病变中，这就提出了肿瘤产生的可溶性MICA/B对NKG2D表达的影响的问题。本研究检测了慢性肝病和肝细胞癌（HCC）中可溶性MICA/B及其在HCC经导管动脉栓塞（TAE）期间参与NKG2D免疫细胞表达的情况。慢性肝病和HCC患者的可溶性MICA/B水平明显高于健康志愿者。肝脏疾病的进展和肿瘤的进展是可溶性MICA/B水平的独立决定因素。免疫组化结果显示，MICA/B不仅在HCC组织中表达，在肝硬化肝细胞中也有表达。TAE治疗显著降低血清可溶性MICA水平，但不降低可溶性MICB水平，增加NK细胞和cd8阳性T细胞上NKG2D的表达；可溶性MICA水平变化与NKG2D表达呈负相关。体外实验证实，含mica的血清明显下调NKG2D表达，抑制NKG2D介导的效应细胞功能。综上所述，尽管可溶性MICA/B均来自HCC和癌前肝硬化肝脏，但HCC的治疗干预可以降低可溶性MICA水平，从而上调NKG2D的表达。癌症治疗可能对nkg2d介导的抗肿瘤免疫有有益的影响。

项目成果

Impahed ability of interferon-alpha-primed dendritic cells to stimulate Th1-type CD4 T-cell response in chronic hepatitis C virus infection.

在慢性丙型肝炎病毒感染中，干扰素-α引发的树突状细胞刺激 Th1 型 CD4 T 细胞反应的能力受到损害。

• 发表时间: 2007
• 期刊: J Viral Hepat 14
• 作者: Miyatake H;Kanto T;et. al.
• 通讯作者: et. al.

Innate immunity in type C hepatitis. Hepatitis C virus disease

丙型肝炎的先天免疫。

• 发表时间: 2008
• 作者: Takehara;T.;Hayashi;N
• 通讯作者: N

Innate immunity in type C hepatitis. Hepatitis C virus disease.

丙型肝炎的先天免疫。

• 发表时间: 2008
• 作者: Takehara T;Hayashi N
• 通讯作者: Hayashi N

Regulation of the NKG2D immunoreceptor by soluble MICA during tran scatheter arterial embolization for hepatocellular, carcinoma.

肝细胞癌经导管动脉栓塞期间可溶性 MICA 对 NKG2D 免疫受体的调节。

• 发表时间: 2007
• 作者: Kohga K;Takehara T;et. al.
• 通讯作者: et. al.

Should aged patients with chronic hepatitis C be treated with interferon and ribavirin combination therapy?

老年慢性丙型肝炎患者是否应该接受干扰素和利巴韦林联合治疗？

• 发表时间: 2006
• 期刊: Hepatol.Res. 35
• 作者: Hiramatsu N;Oze T;Tsuda N;Kurashige N;Koga K;Toyama T;Yasumaru M;Kanto T;Takehara T;Kasahara A;Kato M;Yoshihara H;Katayama K;Hijioka T;Hagiwara H;Kubota S;Oshita M;Haruna Y;Mita E;Suzuki K;Ishibashi K;Hayashi N.
• 通讯作者: Hayashi N.