CYTOTOXIC T-CELL TRANSFER FOR THERAPY OF EBV-LYMPHOMA

EB病毒相关的移植后淋巴组织增生性疾病 （EBV-PTL）是为数不多的人类恶性肿瘤之一， 与免疫功能紊乱有关。致命性EBV-PTL的发生率取决于 很大程度上取决于移植后免疫抑制的程度， 20%来自无关供体或来自HLA的骨髓移植受者 抗原不匹配的家庭成员。这种疾病的肿瘤细胞具有 核型正常，细胞表面表型和病毒基因相似 表达至永生化淋巴母细胞系（LCL）， 在体外用EBV感染B淋巴细胞后建立。 LCL是 对HLA限制性EBV特异性细胞毒性杀伤非常敏感 T淋巴细胞（CTL），在骨髓受体中无法检测到的细胞 在移植后的时期。我们首先假设，EBV-LPD应该 通过重建易感患者与供体来源的 EB病毒特异性CTL，其次是如果CTL被转导标记 与新霉素抗性基因，他们的命运和功能后输注 可以被监控。这些假设将在以下三个方面得到检验： 具体目标： 1.建立EB病毒特异性、基因标记的供者源性细胞毒T细胞 可以在体内有效监测功能的线， 寿命和功能。 2.为了确定输注BMT供体来源的EBV特异性抗体的安全性， 新霉素耐药基因标记的细胞毒性T淋巴细胞 移植了来自匹配的、无关的或不匹配的骨髓的患者 白血病的家庭成员 3. 评价EB病毒特异性CTL的存活率和免疫效果 在骨髓移植人群中， 移植淋巴组织增生性疾病

Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTL) is one of the few human malignancies that is unequivocally related to immune dysfunction. The incidence of fatal EBV-PTL depends largely on the degree of post-transplant immunosuppression and may exceed 20% in recipients of bone marrow grafts from unrelated donors or from HLA antigen mismatched family members. The tumor cells in this disease have a normal karyotype and are similar in cell surface phenotype and virus gene expression to the immortalized lymphoblastoid cell lines (LCLs) that are established after infection of B lymphocytes with EBV in vitro. LCLs are exquisitely sensitive to killing by HLA-restricted EBV-specific cytotoxic T lymphocytes (CTLs), cells that cannot be detected in marrow recipients in the post-transplant period. We hypothesize first, that EBV-LPD should be prevented by reconstitution of susceptible patients with donor-derived EBV-specific CTLs and second that if the CTLs are marked by transduction with a neomycin resistance gene, their fate and function after infusion can be monitored. These hypotheses will be tested in the following three specific aims: 1. To establish donor-derived, gene-marked, EBV-specific cytotoxic T cell lines which can effectively be monitored in vivo with regard to function, longevity and function. 2. To determine the safety of infusions of BMT donor derived EBV-specific cytotoxic T lymphocytes marked with the neomycin-resistance gene in patients transplanted with marrow from a matched unrelated or mismatched family member for leukemia. 3. To evaluation survival and immunological efficacy of EBV-specific CTL in a bone marrow transplant population with high incidence of post- transplant lymphoproliferative disorders.