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Production of antibodies to inhibit the cytotoxic activities of hepatitis C virus-specific cytotoxic T cells

生产抑制丙型肝炎病毒特异性细胞毒性 T 细胞细胞毒活性的抗体

基本信息

批准号：
03557035
负责人：
IMAWARI Michio
金额：
$ 8.38万
依托单位：
Jichi Medical School (1993)The University of Tokyo (1991-1992)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03557035/
关键词：
Hepatitis C Hepatitis C virus Cytotoxic T cell T cell receptor Antibody HLAB44 C型肝炎ウイルスコア抗原

项目摘要

To elucidata the pathogenesis of hepatitis C and apply them to the treatment, we planned to produce antibodies to the variable regions or antigen-binding regions of the T cell receptor of hepatitis C virus-specific cytotoxic T cells to inhibit the cytotoxic activities. We screened cDNA library of a T cell clone TA-NB-2 to obtain the cDNA of T cell receptor beta chain. The TA-NB-2 cells lysed hepatocyts from patients with hepatitis C in an HLA-unrestricted manner. It turned out to be that there existed at least 3 different T cell receptors in TA-NB-2 cells, suggestig that they were not monoclonal. Then we studied the T cell receptor usage of liver infiltrating T cells of hepatitis C patients. We established T cell clones from the liver infiltrating T cells of 5 patients with hepatitis C.In one patients, Vbeta2, Vbeta6.1-3, and Vbeta7 were used preferentially. We also generated HLA B44-restricted cytotoxic T cells recognizing hepatitis C virus core antigen amino acid reidues 88 to 96 from peripheral blood lymphocytes of a patient with hepatitis C.We succeeded in cloning the HLA B44-restricted hepatitis C virus-specific cytotoxic T cells. We will analyze the T cell receptor, clone the cDNA of T cell receptor, express the T cell receptor, and generate the antibodies to inhibit the cytotoxic activities of the cytotoxic T cell clones by binding to the T cell receptor.

为了阐明丙型肝炎的发病机制并将其应用于治疗，我们计划产生针对丙型肝炎病毒特异性细胞毒性T细胞的T细胞受体的可变区或抗原结合区的抗体，以抑制其细胞毒性活性。我们从T细胞克隆TA-NB-2的cDNA文库中筛选T细胞受体β链的cDNA。TA-NB-2细胞以HLA非限制性方式裂解丙型肝炎患者的肝细胞。结果表明，TA-NB-2细胞中至少存在3种不同的T细胞受体，提示它们不是单克隆的。并对丙型肝炎患者肝脏浸润性T细胞的T细胞受体利用进行了研究。我们从5例丙型肝炎患者的肝脏浸润性T细胞中建立了T细胞克隆。在1例患者中，优先使用Vbeta 2，Vbeta6.1-3和Vbeta 7。我们还产生了HLA B44限制性细胞毒性T细胞识别丙型肝炎病毒核心抗原氨基酸残基88至96从外周血淋巴细胞的丙型肝炎患者。我们成功地克隆了HLA B44限制性丙型肝炎病毒特异性细胞毒性T细胞。我们将对T细胞受体进行分析，克隆T细胞受体的cDNA，表达T细胞受体，并通过与T细胞受体结合来产生抗体，从而抑制细胞毒性T细胞克隆的细胞毒性活性。