ADOPTIVE IMMUNOTHERAPY FOR POSTTRANSPLANT EBV LYMPHOMA

移植后 EBV 淋巴瘤的过继免疫治疗

基本信息

批准号：
6172684
负责人：
KENNETH G LUCAS
金额：
$ 18万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2003-08-31
项目状态：
已结题

项目摘要

EBV specific cytotoxic T cells (CTL) have been shown to be effective in preventing and treating EBV induced lymphoproliferative disease in stem cell transplant patients, and adoptive immunotherapy with HLA identical donor lymphocytes has also been applied to an organ transplant patient with this disorder, resulting in complete remission of the disease. The present proposal is to administer HLA identical or haplo-identical EBV CTL to organ transplant patients with EBV-LPD and to monitor these patients for clinical and radiographic response. Patient peripheral blood specimens will be examined post infusion using minisatellite PCR analysis for the presence of donor lymphocyte DNA. Donor CTL will be immunophenotyped at intervals post-infusion. EBV specific cytotoxic T lymphocyte precursor frequencies will be obtained at intervals post infusion. The nature of the cytotoxic response will be evaluated from patient calls as well as donor EBV CTL with regard to MHC restriction, the degree of inhibition of cytotoxicity with monoclonal antibodies directed against Class I, HLA-DR, and CD-3, and the role of B-7/CD28 co-stimulation in the expansion of donor CTL and in patient CTL responses to EBV. The T cell receptor (TCR) VB phenotype will be characterized on infused T cells as well as on patient lymphocytes to correlate disease status, in vitro CTL response, and TCR repertoire. EBV CTL will also be cultivated from EBV sero-negative donors and cord blood mononuclear cells to examine the immune response to EBV BLCL in individuals without a prior infection with this virus. As part of this goal, patient lymphocytes will also be cultured with autologous EBV BLCL to expand populations of EBV reactive CTL. Cloned as well a polyclonal EBV CTL obtained from patients will be expanded with submitogenic doses of CD3 and CD28, with the goal of expanding sufficient number of these cells that could be potentially used for therapeutic infusion. Semi-quantitative EBV PCR will be performed on all organ transplant patients for one year post transplant at monthly intervals in order to determine a correlation between then presence of EBV-LPD and elevated levels of EBV DNA from peripheral blood lymphocytes. This test may be useful in early diagnosis of EBV-LPD in these patients, at a time when their lymphoproliferations are more likely to be controlled by decreased immunosuppression.

EBV特异性细胞毒性T细胞（CTL）已显示为有效预防和治疗EBV诱导干细胞移植患者的淋巴增生性疾病， HLA相同的供体淋巴细胞的收养免疫疗法具有也将其应用于器官移植患者疾病，导致疾病完全缓解。这目前的建议是管理HLA相同或单plo的建议 EBV CTL向器官移植患者EBV-LPD患者，并监测这些患者进行临床和影像学反应。病人外周血标本将在输注后使用 Minisatellite PCR分析供体淋巴细胞的存在脱氧核糖核酸。供体CTL将在输注后间隔进行免疫表型。 EBV特异性细胞毒性T淋巴细胞前体频率将是输注后以隔离时间获得。细胞毒性的性质将从患者呼叫以及捐助者EBV中评估响应 CTL关于MHC限制，抑制程度用针对I类的单克隆抗体的细胞毒性， HLA-DR和CD-3，以及B-7/CD28共刺激在供体CTL和患者CTL对EBV的反应的扩展。 t 细胞受体（TCR）VB表型将在注入的情况下进行表征 T细胞以及患者淋巴细胞以相关性疾病状态，体外CTL响应和TCR曲目。 EBV CTL会也可以从EBV血清阴性供体和脐带血中种植单核细胞检查对EBV BLCL的免疫反应没有事先感染该病毒的个体。作为这个目标，患者淋巴细胞也将与自体EBV BLCL扩大EBV反应性CTL的种群。克隆以及从患者获得的多克隆EBV CTL将是以CD3和CD28的提交生成剂量扩展，目的是扩大足够数量的这些细胞可能是可能用于治疗输注。半定量EBV PCR将对所有器官移植患者进行一年以每月间隔进行移植，以确定 EBV-LPD的存在与升高的水平之间的相关性外周血淋巴细胞的EBV DNA。该测试可能有用在这些患者的EBV-LPD早期诊断中它们的淋巴结增生更可能由免疫抑制减少。