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T-CELL IMMUNOTHERAPY OF EBV ASSOCIATED LYMPHOMA

EBV 相关淋巴瘤的 T 细胞免疫治疗

基本信息

批准号：
2667981
负责人：
Martin J Cannon
金额：
$ 9.11万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2000-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2667981
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

项目摘要

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，获得性淋巴增生性疾病 (LPD) 患者出现的免疫缺陷。 EBV 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病例淋巴瘤和 LPD。正常人的潜伏性 EBV 感染是由 EBV 特异性 CD8+ T 细胞监测和 EBV 相关性控制因此，免疫缺陷患者中的淋巴瘤和 LPD 被认为是由 EBV特异性T细胞免疫受损的结果。根据这些观察结果，本提案将探讨使用 SCID/hu 进行 EBV 特异性 CD8+ T 细胞免疫治疗的潜力 EBV 相关人 B 细胞 LPD 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中。该提案本质上只有一个目标：的产生特征化的 EBV 特异性 T 细胞系或克隆可以抑制或逆转 SCID/hu 小鼠中 EBV 驱动的肿瘤发展。两种方法将被考虑： 1. 将 EBV 特异性人 CD8+ T 细胞转移至 SCID 小鼠注射 EBV 引起的自体 EBV 诱导的人 B 细胞肿瘤转化的类淋巴母细胞系（LCL）。 2. EBV 特异性小鼠 CD8+ T 细胞的转移。 HLA A2.1/Kb 转基因小鼠将准备好产生 EBV 特异性 T 细胞反应识别表达 HLA A2.1 的 LCL。这一战略的主要内容是允许同种 T 细胞转移实验的优点，促进长期 EBV 特异性 T 的重建和评估严重免疫缺陷情况下的细胞免疫。 T 细胞特异性和功能将被表征，并且机制将研究肿瘤抑制作用。 T 细胞将被转移至不同时间评估疾病早期或晚期的治疗； EBV特异性T细胞免疫的预防重建也将是调查了。增强 T 细胞植入的策略将探索体内功能。本研究中确立的原则将提供有价值的合理设计 T 细胞免疫疗法的信息在该环境中预防或治疗 EBV 相关 LPD 和淋巴瘤获得性免疫缺陷，尤其是移植受者艾滋病患者。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preferential utilization of the perforin/granzyme pathway for lysis of Epstein-Barr virus-transformed lymphoblastoid cells by virus-specific CD4+ T cells.

病毒特异性 CD4 T 细胞优先利用穿孔素/颗粒酶途径裂解 Epstein-Barr 病毒转化的淋巴母细胞。

DOI：
10.1006/viro.2001.1020
发表时间：
2001
期刊：
Virology.
影响因子：
0
作者：
Khanolkar,A;Yagita,H;Cannon,MJ
通讯作者：
Cannon,MJ

Evidence for a type 2 bias in the CD8+ T-cell response to Epstein-Barr virus following heart transplantation.

心脏移植后 CD8 T 细胞对 Epstein-Barr 病毒反应存在 2 型偏倚的证据。

DOI：
10.1016/s0041-1345(98)00183-3
发表时间：
1998
期刊：
Transplantation proceedings
影响因子：
0.9
作者：
Cannon,MJ;Reed,LD;Mawulawde,K
通讯作者：
Mawulawde,K

Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer.

DOI：
10.1038/sj.bjc.6600026
发表时间：
2002-01-07
期刊：
BRITISH JOURNAL OF CANCER
影响因子：
8.8
作者：
Santin, A D;Bellone, S;Ravaggi, A;Roman, J J;Pecorelli, S;Parham, G P;Cannon, M J
通讯作者：
Cannon, M J

Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.

人乳头瘤病毒 E7 特异性 CD8 细胞毒性 T 淋巴细胞表达 CD56 与细胞内穿孔素表达增加和针对 HLA-A2 匹配的宫颈肿瘤细胞的细胞毒性增强相关。

DOI：
发表时间：
2001
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Santin,AD;Hermonat,PL;Ravaggi,A;Bellone,S;Roman,JJ;Jayaprabhu,S;Pecorelli,S;Parham,GP;Cannon,MJ
通讯作者：
Cannon,MJ

In vitro induction of tumor-specific human lymphocyte antigen class I-restricted CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients with advanced ovarian cancer.

通过来自晚期卵巢癌患者的卵巢肿瘤抗原脉冲的自体树突状细胞体外诱导肿瘤特异性人淋巴细胞抗原 I 类限制性 CD8 细胞毒性 T 淋巴细胞。