CHARACTERIZATION OF TCR Vβ REPERTOIRE AND TH1/TH2 CYTOKINE RELEASE OF TUMOR-SPECIFIC CYTOTOXIC T CELLS

肿瘤特异性细胞毒性 T 细胞的 TCR Vβ 库和 TH1/TH2 细胞因子释放的表征

• 批准号: 09671340
• 负责人: ARUGA Atsushi
• 金额: $ 2.3万
• 依托单位: TOKYO WOMEN'S MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671340/
• 关键词: TCR Vβ; CTL; Dendritic cell; Cytokine; Immunotherapy; サイトカイン; 樹状細胞; 抗原ペプチド; TCRVβ; 免疫療法

In animal study, tumor-primed lymph node cells or splenocyte activated with tumor or anti-CD3 plus IL-2 mediated tumor regression in adoptive immunotherapy models and release tumor-reactive Type 1 cytokines in tumor specific manner. These cytotoxic T cells (CTL) consist of the several TCR Vβ subpopulations. The majority of the whole population were composed of Vβ3, 5, 7, 8 and 11+cells. TCR Vβ8+cells released high amounts of IFNγ with minimal amounts of IL-10 in response to tumor and mediated tumor regression in vivo. In contrast, TCR Vβ5, 7, 11+cells released low amounts of IFNγ with high level of IL-10 and had no in vivo antitumor reactivity. In human study, tumor-specific CTLs could be generated with tumor lysate or synthetic peptide-pulsed dendritic cells in vitro. These CTLs released high amount of IFNγ with minimal amounts of IL-10 and mediated tumor lysis in vitro cytotoxic assay. TCR Vβ usage of the patients with synthetic peptide-pulsed dendritic cell as cancer vaccine indicated the different profiles of TCR Vβ usage after vaccination. In this study, I demonstrated that Th1/Th2 cytokine patterns are expressed by immune T cells based upon TCR Vβ usage in mouse and human. Selective activation of effective Vβ subpopulation would be required for adoptive immunotherapy.

在动物实验中，在过继免疫治疗模型中，肿瘤引发的淋巴结细胞或脾细胞被肿瘤或抗cd3 + IL-2介导的肿瘤消退激活，并以肿瘤特异性方式释放肿瘤反应性1型细胞因子。这些细胞毒性T细胞（CTL）由几个TCR Vβ亚群组成。整个群体大部分由Vβ3、5、7、8和11+细胞组成。在体内，TCR Vβ8+细胞释放大量IFNγ和少量IL-10，响应肿瘤和介导的肿瘤消退。相比之下，TCR v β 5,7,11 +细胞释放少量IFNγ，高水平IL-10，无体内抗肿瘤反应性。在人体研究中，肿瘤特异性ctl可以在体外用肿瘤裂解液或合成肽脉冲树突状细胞生成。在体外细胞毒实验中，这些ctl释放大量IFNγ和少量IL-10，介导肿瘤溶解。合成肽脉冲树突状细胞作为肿瘤疫苗的患者的TCR Vβ使用情况表明接种后TCR Vβ的使用情况不同。在这项研究中，我证明了基于小鼠和人的TCR Vβ使用，免疫T细胞表达Th1/Th2细胞因子模式。过继免疫治疗需要选择性激活有效的Vβ亚群。

项目成果

Atsushi Aruga, Etsuko Aruga, Keishi Tanigawa, D.Keith Bishop, Vernon K.Sondak, and Alfred E.Chang: "Type 1 versus Type 2 cytokine release by Vβ T cell subpopulations determines in vivo antitumor reactivity."J Immunology. 159. 664-673 (1997)

Atsushi Aruga、Etsuko Aruga、Keishi Tanikawa、D.Keith Bishop、Vernon K.Sondak 和 Alfred E.Chang：“Vβ T 细胞亚群释放的 1 型与 2 型细胞因子决定了体内抗肿瘤反应性。”J 免疫学 159。 664-673 (1997)

Atsushi Aruga: "Different cytokine profiles released by CD4+ and CD8+ tumor-draining lymph node cells involved in mediating tumor regression"Journal of Leukocyte Biology. 61. 507-516 (1997)

Atsushi Aruga：“CD4 和 CD8 肿瘤引流淋巴结细胞释放的不同细胞因子谱参与介导肿瘤消退”白细胞生物学杂志。

有賀淳: "MUC-1ペプチド提示樹状細胞を用いたCTLの誘導"Biotherapy. 13(5). 547-549 (1999)

Atsushi Ariga：“使用 MUC-1 肽呈递树突状细胞诱导 CTL”生物疗法 13(5) (1999)。

有賀淳: "樹状細胞を用いたCTLの抗腫瘍効果増強"Biotherapy. 12(5). 875-877 (1998)

Atsushi Ariga：“使用树突状细胞增强 CTL 的抗肿瘤作用”生物疗法 12(5) (1998)。

Atsushi Aruga, Yoshihito Kodera, Takashi Hatori, Takaji Furukawa, and Ken Takasaki: "Induction of MUC-1 specific CTL stimulated with peptide-pulsed dendritic cells."Biotherapy. 13(5). 547-549 (1999)

Atsushi Aruga、Yoshihito Kodera、Takashi Hatori、Takaji Furukawa 和 Ken Takasaki：“用肽脉冲树突状细胞刺激 MUC-1 特异性 CTL 的诱导。”生物疗法。