T-CELL IMMUNOTHERAPY OF EBV ASSOCIATED LYMPHOMA

EB病毒(EBV)与淋巴瘤密切相关。 获得性淋巴增生性疾病(LPD) 免疫缺陷。EB病毒与大多数与艾滋病有关的疾病有关 免疫母细胞性淋巴瘤和几乎所有移植后病例 淋巴瘤和洛克希德病。正常人中潜伏的EBV感染是 由EBV特异性CD8+T细胞监控和EBV相关 因此，免疫缺陷者的淋巴瘤和LPD被认为是一种 EBV特异性T细胞免疫功能受损所致。 根据这些观察，这项建议将探讨 利用SCID/HU进行EBV特异性CD8+T细胞免疫治疗的可能性 EB病毒相关性人B细胞狼疮小鼠模型。SCID/HU小鼠 与EBV相关的大细胞免疫母细胞淋巴瘤非常相似 出现在免疫缺陷者身上。 这项提议本质上只有一个目标：生产油井- 特征化的EBV特异性T细胞系或克隆可以抑制或 逆转EB病毒驱动的SCID/HU小鼠肿瘤生长。两种方法 将考虑： 1.EBV特异性人CD8+T细胞向SCID小鼠的转移 自体EB病毒诱发的人B细胞肿瘤的研究 转化的淋巴母细胞系(LCL)。 2.EBV特异性小鼠CD8+T细胞的转移人类白细胞抗原A2.1/KB转基因 小鼠将被准备给予和EBV特异性T细胞反应 识别表达HLAA2.1的LCL。这一战略具有重大意义 允许进行同种T细胞移植实验的优势， 促进长期EBV特异性T细胞的重建和评估 在严重免疫缺陷的情况下的细胞免疫。 将表征T细胞的特异性和功能，以及T细胞的机制 将对肿瘤抑制进行研究。T细胞将在 评估早期或晚期疾病治疗的不同时间； EBV特异性T细胞免疫的预防重建也将是 调查过了。加强T细胞植入和治疗的策略 在体内的功能将被探索。 这项研究中确立的原则将提供有价值的 T细胞免疫疗法的合理设计 环境中EBV相关性LPD和淋巴瘤的预防或治疗 获得性免疫缺陷，尤其是移植受者和 艾滋病患者。

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.