Serious Hazards of Transfusion & Cellular Therapies: Mechanisms and Intervention

该计划项目拨款(PPG)申请是埃默里输血和细胞疗法中心的一项综合努力，旨在开展一项重大的、跨学科的和协同的研究工作，以提高戴尔输血的安全性和有效性，特别是在免疫受损的输血接受者中。中心主题是解决输血医学中几个最严重的致病和死亡原因的机制和减轻其影响，包括细胞疗法后的GVHD，包括巨细胞病毒在内的机会性和输血传播感染，以及多次输血受者的红细胞抗原免疫。每个项目都使用创新的方法、战略和/或技术来解决这一中心主题，包括疫苗强化(项目1)和药物改良(项目3)捐赠者淋巴细胞输注、核酸检测和自动毛细管细胞仪白细胞计数(项目2)，以及能够逐步分析RBG免疫的细胞和分子途径的基因工程小鼠模型(项目4)。简而言之，项目1通过开发一种新的方法，将供者淋巴细胞输注(DLI)与有效的基于李斯特菌的疫苗接种策略相结合，以小鼠骨髓移植模型为基础，扩展了我们之前的研究。项目2是一项多医院试验，与更基本的实验室研究一起提出，旨在验证预防通过输血传播的GMV感染的优化方法。项目3用小鼠骨髓移植模型扩展了我们之前的研究，并在人类身上采用了一种新的策略来过继转移抗原特异性供体T细胞，而不会导致致命性GVHD。项目4利用我们实验室开发的一种新的小鼠红细胞免疫模型来识别调节对输注的红细胞的免疫反应的细胞和分子事件。PPG的调查团队横跨公共卫生、肿瘤学、血液学、儿科学和血库学科，并共同努力创建了一系列协同提案。由于这4个项目中的每一个都涉及输血医学中的重要细胞和免疫学事件，项目的完成将导致新的、改进的输血和移植治疗成分和/或保护高危输血接受者的战略。项目的成功执行将得到三个核心的推动，包括一个行政核心(核心A)、一个免疫和病毒学监测实验室核心(核心B)和一个生物统计和数据管理GORE(核心G)。

This program project grant (PPG) application is an integrative endeavor by the Emory Center for Transfusion and Cellular Therapies to institute a major, interdisciplinary, and synergistic research effort to improve the safety and effectiveness of blood dell transfusions, particularly in immuno-compromised transfusion recipients. The central theme is to address mechanisms of, and mitigate the effects of, several of the most serious causes of morbidity and mortality in transfusion medicine, including GVHD following cellular therapies, opportunistic and transfusion-transmitted infections including CMV, and immunization to RBC antigens in recipients of multiple transfusions. Each project uses innovative and novel approaches, strategies and/or technologies to address the central theme including vaccine enhanced- (Project 1) and pharmacologically modified- (Project 3) donor lymphocyte infusions, nucleic acid testing and automated capillary cytometric leukocyte counting (Project 2), and a genetically engineered murine model allowing a step-by-step analysis of the cellular and molecular pathways to RBG immunization (Project 4). In brief, Project 1 extends our previous studies with a mouse BMT model by developing a novel method of combining donor lymphocyte infusion (DLI) with an effective listeria-based vaccination strategy. Project 2 is a multihospital trial, proposed in conjunction with more basic laboratory studies, designed to validate optimized methods to prevent transfusion-transmitted GMV infections. Project 3 extends our previous studies with a mouse BMT model and employs in humans a novel strategy to adoptively transfer antigen-specific donor T-cells without inducing lethal GVHD. Project 4 utilizes a novel murine model of RBC immunization developed in our laboratories to identify the cellular and molecular events that regulate immune responses to transfused RBC. The team of investigators in the PPG spans Public Health, Oncology, Hematology, Pediatrics, and Blood Banking disciplines and has worked together to create a series of synergistic proposals. As each of these 4 projects addresses important cellular and immunologic events in Transfusion Medicine, project completion should lead to novel, improved transfusion and transplantation therapeutic components and/or strategies to protect high-risk transfusion recipients. The successful execution of the Projects will be facilitated by three Cores including an Administrative Core (Core A), an Immunologic and Virologic Monitoring Laboratory Core (Core B), and a Biostatistics and Data Management Gore (Core G).