Novel immunogene therapy for hematopoietic malignancies

造血系统恶性肿瘤的新型免疫基因疗法

• 批准号: 15390301
• 负责人: YASUKAWA Masaki
• 金额: $ 9.41万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390301/
• 关键词: hematopoietic malignancies; cytotoxic T lymphocyte; WT1; cancer vaccine; immunodefcient mice; T-cell receptor; 白血病; 免疫療法; パーフォリン; 骨髄腫

We performed studies on immunogene therapy for hematopoietic malignanicies. The data obtained from the series of study are as follows. 1) Myeloma cells are sensitive to perforin-dependent cytotoxicity mediated by WT1-specifici cytotoxic T lymphocytes (CTLs). 2)There is a difference in the control of perforin expression between CD4^+ and CD8^+ CTLs ; that is, perforin is expressed constitutively in memory CD8^+ CTLs, but is dependent on cell activation in memory CD4^+ CTLs. 3)T-cell receptor (TCR) α and β genes obtained from an HLA-A24-restricted, WT1 peptide-specific CTL clone were lentivirally transduced to polyclonally-activated T lymphocytes. TCR gene-transduced CD4+ and CD8+ T lymphocytes showed HLA-A24-restricted and WT1-specific reactivity against leukemia cells. 4)The WT1-derived epitope recognized by HLA-DP5-restricted CD4+ T-cell clone was identified. WT1-specific CD4+ T-cell clone exerted the perforin-dependent cytotoxicity against leukemia cells. 5)Phase I clinical study of cancer peptide vaccine using WT1-derived and hTERT-derived peptides has been continued. 6) Human immune system was constructed in the novel immundeficient mice by transplantation of human hematopoietic stem cells.

我们开展了针对血液系统恶性肿瘤的免疫基因治疗研究。从该系列研究中获得的数据如下。1)骨髓瘤细胞对WT1特异性细胞毒性T淋巴细胞(CTL)介导的穿孔素依赖的细胞毒反应敏感。2)CD4^+和CD8^+CTL对穿孔素表达的调控存在差异，即在记忆性CD8^+CTL中呈结构性表达，而在记忆性CD8^+CTL中则依赖于细胞的激活。3)从人类白细胞抗原A24限制性T细胞受体基因克隆中获得T细胞受体α和β基因。TCR基因转导的CD4+和CD8+T细胞对白血病细胞表现出HLA-A24限制性和WT1特异性反应。4)确定了人类白细胞抗原DP5限制性CD4+T细胞克隆识别的WT1表位。WT1特异性的CD4+T细胞克隆对白血病细胞具有穿孔素依赖的细胞毒作用。5)WT1来源和hTERT来源的抗癌多肽疫苗的第一阶段临床研究仍在继续。6)通过移植人造血干细胞构建了新型免疫缺陷小鼠的人免疫系统。

项目成果

Generation of human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes.

通过使用肿瘤肽特异性 T 细胞受体基因进行细胞工程，生成人类肿瘤特异性、HLA I 类限制性 Th1 和 Tc1 细胞。

• 发表时间: 2005
• 期刊: Blood 106
• 作者: Tsuji T;Yasukawa M;Matsuzaki J;Ohkuri T;Chamoto K;Wakita D;Azuma T;Niiya H;Miyoshi H;Kuzushima K;Oka Y;Sugiyama H;Ikeda H;Nishimura T.
• 通讯作者: Nishimura T.

Yanai, F., Yasukawa, M., et al.: "Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4^+ T lymphocytes : analysis using the combination of hereditary perforin-deficient effector cells and fas-deficient target cells"J.Immunol.

Yanai, F., Yasukawa, M., et al.：“穿孔素在人 CD4^ T 淋巴细胞介导的抗原特异性细胞毒性中的重要作用：使用遗传性穿孔素缺陷效应细胞和 fas 缺陷靶细胞的组合进行分析”

Identification of novel MUNC13-4 mutations in familial hemophagocytic lymphohistiocytosis and functional analysis of MUNC 13-4-deficient cytotoxic T lymphocytes.

家族性噬血细胞性淋巴组织细胞增多症中新型 MUNC13-4 突变的鉴定以及 MUNC 13-4 缺陷型细胞毒性 T 淋巴细胞的功能分析。

• 发表时间: 2004
• 期刊: J.Med.Genet. 41
• 作者: Yamamoto;K.;Ishii;E.;Sako;M.;Ohga;S.;Furuno;K.;Suzuki;N.;Ueda;I.;Imayoshi;M.;Yamamoto;S.;Morimoto;A.;Takada;H.;Hara;T.;Imashuku;S.;Sasazuki;T.;Yasukawa;M.
• 通讯作者: M.

Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4[+] T lymphocytes : analysis using the combination of hereditary perforin-deficient effector cells and Fas-deficient target cells

• 发表时间: 2004
• 期刊: The Journal of Immunology
• 作者: 柳井 文男

Human cord blood- and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells

• DOI: 10.1096/fj.04-2396fje
• 发表时间: 2004-10-01
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Ishikawa, F;Yasukawa, M;Harada, M
• 通讯作者: Harada, M