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Adoptive Immunotherapy for Malignant Brain Tumors Using Killer T Lymphocytes Enhanced by Interferon Gamma Gene Transfer

使用干扰素 γ 基因转移增强的杀伤性 T 淋巴细胞对恶性脑肿瘤进行过继免疫治疗

基本信息

批准号：
62480307
负责人：
YAMASHITA Junkoh
金额：
$ 3.9万
依托单位：
Kanazawa University (1988-1989)Kyoto University (1987)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1988
项目状态：
已结题

项目摘要

A mouse ihterfebon (IFN) gamma CDNA was transferred to mouse neuroblastoma cell line, C1300 of A/Jax origin, with a chimeric retrovirus containing the IFN gamma gene. Two infected subclones C-gamma-3 and C-gamma-22 were obtained as a low and a high producers, respectively. These subclones were similar to the original clone in respects of in vitro growth pattern, morphology, and antigen expression of neurofilaments, except the expression of major hisiocompatibility complex (MHC) class I antigens, which were extremely augmented at the surface expression level as well as at the transcription level, regardless the difference in amount of their IFN-gamma production. The in vivo tumorigenicity was reduced in the high producer, C-gamma-22, but not in the low producer, C-gamma-3. The in vivo tumor growth rate was suppressed in both subclones, as compared to the parental line. It was therefore suggested that the suppression of tumor formation is more closely associated with constitutive IFN-gam … More ma production rather than the MHC antigen expression, and that the tumor growth rate is affected by the high expression of the surface antigens.As a next step, the cDNA encoding mouse IFN-gamma was transferred into a specific cytotoxic T lymphocyte (CTL) clone, designated E-4, against 203-glioma (a 20- methylcholanthrene-induced glioma line of C57/BL mouse origin). The efficacy of IFN-gamma production from the exogenous gene on augumeniation of tumor targeting was confirmed. Out of five, two gene-transferred subclones constitutively produced 8 to 10 times higher amount of IFN-gamma as compared with the parental E-4. Correspondingly, these two subclones exhibited 2 to 3 times higher killing activity against 203-glioma as compared with the parental line. It was thought that tumor cells, in the vicinity of the constitutively IFN-gamma-producing CTLs, may be stimulated to induce or enhance the expression of surface antigens, including the MHC antigens as well as the tumor associated antigens relevant to immune recognition.In summary, it was hopefully suggested that retrovirus-mediated transfer of cytokine genes would be useful for a modified immunotherapy of cancer. Less

用含有IFN γ基因的嵌合逆转录病毒将小鼠IFN γ cDNA转移到A/Jax来源的小鼠神经母细胞瘤细胞系C1300中。获得了两个感染的亚克隆C-gamma-3和C-gamma-22，分别作为低生产者和高生产者。这些亚克隆在体外生长模式、形态和神经丝的抗原表达方面与原始克隆相似，除了主要组织相容性复合物（MHC）I类抗原的表达，其在表面表达水平以及转录水平上极大地增强，而不管它们的IFN-γ产生量的差异。体内致瘤性在高生产者C-γ-22中降低，但在低生产者C-γ-3中不降低。与亲本细胞系相比，两个亚克隆的体内肿瘤生长速率均受到抑制。因此，提示肿瘤形成的抑制与组成性IFN-γ更密切相关。 ...更多信息作为下一步，将编码小鼠IFN-γ的cDNA转移到特异性细胞毒性T淋巴细胞（CTL）克隆中，命名为E-4，其针对203-胶质瘤（C57/BL小鼠来源的20-甲基胆蒽诱导的胶质瘤系）。从外源基因产生IFN-γ对增强肿瘤靶向的功效得到证实。在五个中，两个基因转移的亚克隆组成性地产生与亲本E-4相比高8至10倍的IFN-γ量。相应地，这两个亚克隆对203-胶质瘤的杀伤活性比亲本系高2至3倍。人们认为，在组成性产生IFN-γ的CTL附近的肿瘤细胞可以被刺激以诱导或增强表面抗原的表达，包括MHC抗原以及与免疫识别相关的肿瘤相关抗原。少