Mechanisms underlying the harmful effects of stored red blood cell transfusions

描述（由申请方提供）：本研究旨在确定输注储存红细胞的不良反应在多大程度上是由铁急性输送至单核细胞-巨噬细胞系统引起的。尽管输血对治疗症状性贫血有效，但越来越多的证据表明，RBC输注会增加住院患者的感染率、发病率和死亡率。我们在小鼠和人类中的初步数据强烈表明，情况确实如此，铁是产生这些不良影响的最有可能的罪魁祸首。根据目前的FDA标准，如果多达25%的红细胞在24小时内被清除，则储存的红细胞（RBC）单位在临床上可接受用于输血，从而向单核细胞-巨噬细胞系统提供大量的铁剂量。该建议的中心假设是，铁，在吞噬细胞中的细胞内和细胞外作为血浆非转铁蛋白结合铁（NTBI），是与储存的RBC输注相关的不良反应的原因。为了实现我们的目标，我们将使用输血和败血症的良好表征的小鼠模型。本研究有三个具体目的：目的#1：检验细胞内铁水平增加的促氧化作用是输注较旧储存RBC后观察到的促炎状态的原因这一假设。目的#2：检验较旧储存RBC的急性清除改变T辅助（TH）细胞向TH 17细胞分化的假设。目标3：为了检验以下假设，即在急性清除较旧的储存RBC后释放的NTBI增加了单细菌感染和多微生物败血症模型中感染的严重程度。因此，本提案将在目标#1中定义铁损伤的机制，在目标#2中表征对该损伤的免疫应答，并在目标#3中研究该损伤的临床后果。从该项目中获得的见解将指导未来的临床前研究，评估人类输血医学中的新治疗方法。这个项目，沿着一个完善的职业发展计划，包括四个杰出的导师和顾问，将为申请人提供免疫学和铁生物学的培训工具，这将推动他的研究生涯，一个独立的研究者。 公共卫生相关性：该项目的最终目标是确定铁是否是与输注较旧的储存红细胞相关的不良反应的原因。从完成本提案中获得的见解将对当前的输血实践产生影响，并将为开发合理设计的方法以提高人类供体血液和人类输血治疗的质量提供基础。

DESCRIPTION (provided by applicant): This research is designed to determine the extent to which the adverse effects of the transfusion of stored RBCs result from the acute delivery of iron to the monocyte-macrophage system. Although transfusion is effective in treatment of symptomatic anemia, there is increasing evidence that RBC transfusions increase rates of infection, morbidity, and mortality in hospitalized patients. Our preliminary data in mice and humans strongly suggest that this is indeed the case, and that iron is the most likely culprit in producing these adverse effects. By current FDA standards, a unit of stored red blood cells (RBC) is clinically acceptable for transfusion if as much as 25% of the RBC are cleared within 24 hours, thereby delivering a substantial dose of iron to the monocyte-macrophage system. The central hypothesis of this proposal is that iron, acting both intracellularly in phagocytes and extracellularly as plasma non-transferrin bound iron (NTBI), is responsible for the adverse effects associated with stored RBC transfusions. To accomplish our aims, we will use well-characterized mouse models of transfusion and sepsis. This research has three Specific Aims: Aim #1: To test the hypothesis that the pro-oxidant effects of increased intracellular iron levels are responsible for the observed pro-inflammatory state following transfusion of older, stored RBCs. Aim #2: To test the hypothesis that the acute clearance of older stored RBCs alters T helper (TH) cell differentiation towards TH17 cells. Aim #3: To test the hypothesis that NTBI released following the acute clearance of older stored RBCs increases the severity of infection in models of monobacterial infection and polymicrobial sepsis. Thus, this proposal will define the mechanism of the iron insult in Aim #1, characterize the immune response to this insult in Aim #2, and study the clinical consequences of this insult in Aim #3. The insights gained from this project will guide future pre-clinical studies evaluating novel therapeutic approaches in human transfusion medicine. This project, along with a well-developed career development plan, including four distinguished mentors and advisors, will provide the applicant with a training vehicle in immunology and iron biology, which will advance his research career to that of an independent investigator. PUBLIC HEALTH RELEVANCE: The ultimate goal of this project is to determine whether iron is responsible for the adverse effects associated with transfusions of older, stored red blood cells. The insights gained from completing this proposal will have an impact on the current practice of blood transfusion and will provide the foundation for developing rationally- designed approaches to improve the quality of human donor blood and of human transfusion therapy.