CYTOTOXIC T-CELL TRANSFER FOR THERAPY OF EBV-LYMPHOMA

EB病毒相关性移植后淋巴增生性疾病 (EBV-PTL)是为数不多的明确的人类恶性肿瘤之一 与免疫功能障碍有关。致死性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，并可能超过 20%的骨髓移植受者来自无血缘关系的捐赠者或来自人类白细胞抗原 抗原不匹配的家庭成员。这种疾病中的肿瘤细胞有一种 核型正常，细胞表面表型和病毒基因相似 在永生化的淋巴母细胞系(LCLS)中表达 用EB病毒体外感染B淋巴细胞后建立。LCL是 对人类白细胞抗原限制性EBV特异性细胞毒的杀伤高度敏感 T淋巴细胞(CTL)，在骨髓受者中检测不到的细胞 在移植后时期。我们首先假设，EBV-LPD应该 通过对供者来源的易感患者进行重建来预防 EBV特异性CTL；第二，如果CTL被转导标记 带有新霉素抗性基因的人，输注后的命运和功能 可以被监控。这些假设将在以下三个方面得到验证 具体目标： 1.建立供者来源的、基因标记的EBV特异性细胞毒T细胞 能够在体内有效地监测其功能的品系， 寿命长，功能强。 2.确定骨髓移植供者来源的EBV特异性输注的安全性 新霉素耐药基因标记的细胞毒T细胞 从匹配的、无血缘关系的或不匹配的骨髓移植的患者 白血病的家庭成员。 3.评价EBV特异性CTL的存活率和免疫效果 在骨髓移植人群中，后遗症发病率高 移植淋巴增生性疾病。

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.