Establishment of HIV-specific cytotoxic T cells via TCR gene cloning and gene transfer using in vivo information

利用体内信息通过 TCR 基因克隆和基因转移建立 HIV 特异性细胞毒性 T 细胞

• 批准号: 14021015
• 负责人: YAMAMOTO Kazuhiko
• 金额: $ 40.96万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14021015/
• 关键词: HIV; T cells; Cytotoxic T cells; T cell receptor clonality; gene transfer

HIV-specific cytotoxic T cells have been regarded to be an important factor to control HIV infection. However, in the patients infected with HIV, T cell antigen receptor zeta chain down-regulation and impaired in vitro T cell function have been described. This phenomenon could potentially make the development of HIV-specific vaccination difficult. We, therefore, tried to establish alternative HIV-specific immunotherapy.At present, we do not have a sufficient range of strategies for manipulating antigen-specific T cells. We propose that T cell receptor gene transfer could be used for antigen-specific immunotherapy. In the proposed technique, important antigen-specific T cells in patients would first be identified, and then a pair of cDNAs encoding alpha and beta T cell receptors would be isolated from these single T cells. These genes would then be transferred into self lymphocytes. These engineered antigen-specific cells also manipulated to express appropriate functional genes could then be applied to specific immunotherapy.In order to prove this system can work in HIV infection, we used an experimental system, in which immune responses against HIV env gp160 pepetide P18IIIB was elicited in BALB/c mice. We demonstrated that HIV specific CTL could be obtained using TCR gene cloning using the information of TCR clonal analysis and reconstitution of the TCR function by gene transfer.

HIV特异性细胞毒性T细胞被认为是控制HIV感染的重要因素。然而，在感染HIV的患者中，T细胞抗原受体ζ链下调和体外T细胞功能受损已被描述。这种现象可能会使艾滋病毒特异性疫苗的开发变得困难。因此，我们试图建立另一种HIV特异性免疫疗法。目前，我们还没有足够的策略来操纵抗原特异性T细胞。我们建议T细胞受体基因转移可用于抗原特异性免疫治疗。在所提出的技术中，将首先鉴定患者中重要的抗原特异性T细胞，然后从这些单个T细胞中分离出编码α和β T细胞受体的一对cDNA。然后这些基因将被转移到自身淋巴细胞中。为了证明该系统在HIV感染中的有效性，我们在BALB/c小鼠中建立了一个实验系统，在该系统中，我们诱导了针对HIV env gp 160肽P18 IIIB的免疫应答。我们证明，利用TCR克隆分析的信息，通过基因转移重建TCR功能，可以通过TCR基因克隆获得HIV特异性CTL。

项目成果

Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences

• DOI: 10.1002/art.11366
• 发表时间: 2004-01-01
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Kochi, Y;Yamada, R;Yamamoto, K
• 通讯作者: Yamamoto, K

A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autolinmunities.

FCRL3 的功能变异编码 Fc 受体样 3，与类风湿性关节炎和多种自身免疫相关。

• 发表时间: 2005
• 期刊: Nature Genetics. 37
• 作者: Kochi Y.

Sekiya T.et al.: "Variations in the human Th2-specific chemokine TARC gene."Immunogenetics. 54. 742-745 (2003)

Sekiya T.等人：“人类 Th2 特异性趋化因子 TARC 基因的变异。”免疫遗传学。

SLC22A4 and RUNX1: identification of RA susceptible genes

• DOI: 10.1007/s00109-004-0547-y
• 发表时间: 2004-06
• 期刊: Journal of Molecular Medicine
• 作者: R. Yamada;S. Tokuhiro;X. Chang;Kazuhiko Yamamoto

Suzuki K.et al.: "High diagnostic performance of ELISA detection of antibodies to citrullinated antigens in rheumatoid arthritis."Scand J Rheumatol.. 32. 197-204 (2003)

Suzuki K.等人：“类风湿性关节炎中瓜氨酸抗原抗体的 ELISA 检测具有高诊断性能。”Scand J Rheumatol.. 32. 197-204 (2003)