Serious Hazards of Transfusion & Cellular Therapies: Mechanisms and Intervention

该计划项目资助（PPG）申请是埃默里输血和细胞治疗中心的综合奋进，旨在开展一项重大的跨学科和协同研究工作，以提高输血的安全性和有效性，特别是在免疫功能低下的输血接受者中。中心主题是解决输血医学中几种最严重的发病率和死亡率原因的机制，并减轻其影响，包括细胞治疗后的GVHD，机会性和输血传播的感染，包括CMV，以及多次输血接受者的RBC抗原免疫。每个项目都使用创新和新颖的方法、战略和/或技术来解决中心主题，包括疫苗增强-（项目1）及经修改的─（项目3）供者淋巴细胞输注、核酸检测和自动化毛细管细胞计数白细胞计数（项目2），和一个基因工程小鼠模型，允许逐步分析RBG免疫的细胞和分子途径（项目4）。简而言之，项目1通过开发一种将供体淋巴细胞输注（DLI）与有效的基于大肠杆菌的疫苗接种策略相结合的新方法，扩展了我们先前的小鼠BMT模型研究。项目2是一项多医院试验，与更基础的实验室研究相结合，旨在验证预防输血传播GMV感染的优化方法。项目3用小鼠BMT模型扩展了我们以前的研究，并在人类中采用了一种新的策略来过继转移抗原特异性供体T细胞而不诱导致死性GVHD。项目4利用我们实验室开发的一种新型小鼠RBC免疫模型来鉴定调节对输注RBC的免疫应答的细胞和分子事件。PPG的研究人员团队涵盖公共卫生、肿瘤学、血液学、儿科和血库学科，并共同努力制定了一系列协同提案。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，因此项目完成后应产生新的、改进的输血和移植治疗成分和/或策略，以保护高风险输血受者。项目的成功实施将由三个核心促进，包括行政核心（核心A）、免疫学和病毒学监测实验室核心（核心B）以及生物统计学和数据管理戈尔（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).