VACCINATION OF PATIENTS AT RISK FOR POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。EB病毒(Epstein-Barr Virus，EBV)特异性T细胞在整个生命过程中起着控制EBV复制的核心作用。免疫受损患者中EB病毒相关淋巴增生性疾病的发病率大大增加就是证据。此外，在接受异基因骨髓移植的患者中，通过过继转移体外扩增的EBV特异性细胞毒性T细胞来恢复EBV特异性T细胞介导的免疫，已被证明有助于促进移植后淋巴增生性疾病(PTLD)病变的消退。PTLD是导致接受实体器官移植患者发病率和死亡率的主要原因。在这群患者中，用于过继转移的EBV特异性T细胞的来源是非常有问题的。实体器官受者PTLD的自然历史表明，激发对EBV的记忆T细胞反应或增强现有的反应可能会降低这一人群中PTLD的发生率。面对治疗性免疫抑制，强大的多价反应似乎最有可能保持有效。实现这一目标的一种安全可行的方法是使用由自体EBV感染的淋巴母细胞系(LCL)组成的细胞疫苗。EBV感染的自然病史和LCL在体外的免疫原性表明，该细胞疫苗可能是体内EBV特异性T细胞反应的有效刺激因子。这项拟议的研究将在考虑进行实体器官移植的患者中测试由自体EB病毒(EBV)感染的淋巴母细胞系(LCL)组成的疫苗制剂的安全性和有效性。LCL和EB病毒将通过光化学处理被灭活，光化学处理包括盐酸氨基多糖(S-59)和UVA光。40名患者(20名EBV血清阳性和20名血清阴性)将分两次接种，间隔1个月。疗效的主要替代终点将是细胞内细胞因子合成对EBV潜伏抗原的细胞反应。对EBV血清阴性和血清阳性患者的体液反应进行EBV抗原检测。在这项研究的时间过程中，这些因素的耐久性将得到表征。血清阴性患者中的原发感染将成为特征。将描述与拟议的疫苗接种计划相关的不良事件。具体目的-评估由经光化学处理的自体EBV感染的淋巴母细胞组成的疫苗在EBV血清阴性患者中产生EBV特异性T细胞和抗体反应或增强考虑进行实体器官移植的血清阳性患者的反应的有效性。-确定与这种疫苗相关的不良事件-评估疫苗在研究期间保护EBV血清阴性患者免受EBV初级感染的能力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epstein-Barr virus (EBV) specific T cells play a central role controlling the replication of EBV throughout life. This is evidenced by the greatly increased incidence of EBV-associated lymphoproliferative diseases in immunocompromised patients. In addition, restoration of EBV-specific T cell-mediated immunity via adoptive transfer of ex vivo expanded EBV-specific cytotoxic T cells in patients who have undergone allogeneic bone marrow transplantation has been shown to mediate regression of post-transplant lymphoproliferative disorder (PTLD) lesions. PTLD is a major cause of morbidity and mortality in patients who have received solid organ transplants. In this population of patients, the source of EBV-specific T cells for adoptive transfer is highly problematic. The natural history of PTLD in solid organ recipients suggests that elicitation of a memory T cell response against EBV or the augmentation of an existing response is likely to reduce the incidence of PTLD in this population. A robust multivalent response seems most likely to remain effective in the face of therapeutic immunosuppression. A safe and feasible approach to accomplish this goal is the use of a cellular vaccine consisting of autologous EBV-infected lymphoblastoid cell lines (LCLs). The natural history of EBV infection and the immunogenicity of LCL in vitro suggest that this cellular vaccine may be a potent stimulator of EBV-specific T cell responses in vivo. The proposed study will test the safety and efficacy of a vaccine preparation consisting of an autologous Epstein-Barr virus (EBV)-infected lymphoblastoid cell line (LCL) in patients who are being considered for solid organ transplant. The LCL and the EBV will be inactivated by photochemical treatment that consists of amotosalen HCl (S-59) and UVA light. Forty patients (20 EBV seropositive and 20 seronegative) will be vaccinated on two occasions, 1 month apart. The primary surrogate endpoint for efficacy will be cellular responses to EBV latency antigens by intracellular cytokine synthesis. Measurements of humoral responses to EBV antigens will be done in both EBV seronegative and seropositive patients. The durability of these during the time course of this study will be characterized. Primary infection among seronegative patients will be characterized. Adverse events associated with the proposed vaccination scheme will be described. SPECIFIC AIMS - To assess the efficacy of a vaccine consisting of photochemically treated autologous EBV-infected lymphoblastoid cells in generating EBV-specific T cell and antibody responses in EBV seronegative patients or boosting the response in seropositive patients being considered for solid organ transplant. - To identify adverse events associated with such a vaccine - To assess the ability of the vaccine to protect from EBV primary infection in EBV seronegative patients during the time course of the study.