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zeta链下调且体外T细胞功能受损。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，我们试图建立替代性 HIV 特异性免疫疗法。目前，我们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，首先将鉴定患者体内重要的抗原特异性T细胞，然后从这些单个T细胞中分离出一对编码α和β T细胞受体的cDNA。然后这些基因将被转移到自身淋巴细胞中。这些工程化的抗原特异性细胞也被操纵以表达适当的功能基因，然后可以应用于特定的免疫治疗。为了证明这个系统可以在HIV感染中发挥作用，我们使用了一个实验系统，其中针对HIV env gp160肽P18IIIB的免疫反应是在 BALB/c 小鼠中引发。我们证明，利用 TCR 克隆分析的信息和通过基因转移重建 TCR 功能，可以通过 TCR 基因克隆获得 HIV 特异性 CTL。

项目成果

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.

Tahara H.et al.: "Reconstitution of CD8^+ T cells by retroviral transfer of the TCR αβ-chain genes isolated from a clonally expanded P815-infiltrating lymphocyte^1."J Immunol.. 171. 2154-2160 (2003)

Tahara H. 等人：“通过逆转录病毒转移从克隆扩增的 P815 浸润淋巴细胞 ^1 中分离出的 TCR αβ 链基因来重建 CD8^+ T 细胞。”J 免疫学杂志 171. 2154-2160 (2003)

Kawahata K. et al.: "Generation of CD4^+CD25^+ regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression"J. Immunol.. 168. 4399-4405 (2002)

Kawahata K.等人：“从自身反应性T细胞中产生CD4^CD25^调节性T细胞，同时在胸腺中进行阴性选择，并通过内源TCR表达从非自身反应性T细胞中产生CD4^CD25^调节性T细胞”J。

In vivo IL-10 gene delivery suppresses airway eosinophilia and hyperreactivity by down-regulating APC functions and migration without impairing the antigen-specific systemic immune response in a mouse model of allergic airway inflammation1.

在过敏性气道炎症小鼠模型中，体内 IL-10 基因递送通过下调 APC 功能和迁移来抑制气道嗜酸性粒细胞增多和高反应性，而不损害抗原特异性全身免疫反应1。

• 发表时间: 2005
• 期刊: J Immunol. 174
• 作者: Ogawa;M.;Sasakawa;C.;稲岡ダニエル健 et al.;Neumann et al.;Nakagome K. et al.
• 通讯作者: Nakagome K. et al.

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)