T-CELL IMMUNOTHERAPY OF EBV ASSOCIATED LYMPHOMA

EBV 相关淋巴瘤的 T 细胞免疫治疗

• 批准号: 2376932
• 负责人: Martin J Cannon
• 金额: $ 8.76万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2376932
• 关键词: Epstein Barr virus; acquired immunodeficiency; cellular immunity; cytokine; cytotoxic T lymphocyte; gene expression; genetically modified animals; human subject; immunotherapy; laboratory mouse; lymphoma; passive immunization; tissue /cell culture; tissue mosaicism; virus related neoplasm /cancer

Epstein-Barr virus (EBV) is closely associated with the lymphomas and lymphoproliferative disorders (LPD) that arise in patients with acquired immunodeficiency. EBV is associated with the majority of AIDS-related immunoblastic lymphomas and virtually all cases of post-transplant lymphoma and LPD. Latent EBV infection in normal individuals is controlled by EBV-specific CD8+ T cell surveillance, and EBV-associated lymphoma and LPD in the immunodeficient is thus thought to arise as a result of impaired EBV-specific T cell immunity. In the light of these observations, this proposal will explore the potential for EBV-specific CD8+ T cell immunotherapy, using the SCID/hu mouse model of EBV-associated human B cell LPD. The SCID/hu mouse closely resembles the EBV-associated large-cell immunoblastic lymphoma that arise in the immunodeficient. There is in essence a single goal of this proposal; generation of well- characterized EBV-specific T cell lines or clones that can inhibit or reverse EBV-driven tumor development in SCID/hu mice. Two approaches will be considered: 1. Transfer of EBV-specific human CD8+ T cells to SCID mice bearing autologous EBV-induced human B cell tumors arising from injection of EBV- transformed lymphoblastoid cell lines (LCL). 2. Transfer of EBV-specific mouse CD8+ T cells. HLA A2.1/Kb transgenic mice will be primed to give and EBV-specific T cell response that recognizes HLA A2.1-expressing LCL. This strategy has the major advantage of allowing same-species T cell transfer experiments, facilitating reconstitution and evaluation of long-term EBV-specific T cell immunity in the context of severe immunodeficiency. T cell specificity and function will be characterized, and mechanisms of tumor inhibition will be investigated. T cells will be transferred at various times to assess therapy of early or advanced stages of disease; prevention reconstitution of EBV-specific T cell immunity will also be investigated. Strategies for enhancement of T cell engraftment and function in vivo will be explored. The principles established in this study will provide valuable information for the rational design of T cell immunotherapy for prevention or treatment of EBV-associated LPD and lymphoma in the setting of acquired immunodeficiency, most particularly transplant recipients and AIDS patients.

EB病毒（EBV）与淋巴瘤密切相关， 淋巴组织增生性疾病（LPD），出现在患者获得性 免疫缺陷。 EB病毒与大多数艾滋病相关 免疫母细胞淋巴瘤和几乎所有移植后 淋巴瘤和LPD。 正常人的潜伏性EBV感染是 由EBV特异性CD 8 + T细胞监测控制，以及EBV相关 淋巴瘤和LPD在免疫缺陷，因此被认为是作为一个 EBV特异性T细胞免疫受损的结果。 根据这些意见，本提案将探讨 使用SCID/hu的EBV特异性CD 8 + T细胞免疫疗法的潜力 EBV相关的人B细胞LPD的小鼠模型。 SCID/hu小鼠 与EB病毒相关的大细胞免疫母细胞淋巴瘤非常相似 免疫缺陷的人身上 这一计划的目标只有一个，即创造良好的... 特征性的EBV特异性T细胞系或克隆，其可以抑制或 在SCID/hu小鼠中逆转EBV驱动的肿瘤发展。 两种方法 将考虑： 1. 将EBV特异性人CD 8 + T细胞转移至携带CD 8的SCID小鼠 由注射EBV引起的自体EBV诱导的人B细胞肿瘤， 转化的淋巴母细胞系（LCL）。 2. EBV特异性小鼠CD 8 + T细胞的转移。 HLA A2.1/Kb转基因 小鼠将被致敏以产生EBV特异性T细胞应答， 识别表达HLA A2.1的LCL。 这一战略主要 允许同种T细胞转移实验的优点， 促进长期EBV特异性T细胞的重建和评估 严重免疫缺陷背景下的细胞免疫。 T细胞的特异性和功能将被表征，并且 将研究肿瘤抑制。 T细胞将在 不同的时间来评估疾病早期或晚期阶段的治疗; 预防EB病毒特异性T细胞免疫的重建也将是 研究了 用于增强T细胞植入的策略和 将探索体内功能。 本研究所确立的原则将提供有价值的 为T细胞免疫治疗的合理设计提供信息， 在环境中预防或治疗EBV相关的LPD和淋巴瘤 获得性免疫缺陷，特别是移植受体， 艾滋病患者。