Mechanisms underlying the harmful effects of stored red blood cell transfusions

描述(由申请人提供)：这项研究旨在确定输注储存的红细胞的不良影响在多大程度上是由于向单核细胞-巨噬细胞系统急性输送铁造成的。虽然输血对治疗症状性贫血有效，但越来越多的证据表明，输注红细胞会增加住院患者的感染率、发病率和死亡率。我们在老鼠和人类身上的初步数据有力地表明，情况确实如此，铁最有可能是产生这些不良影响的罪魁祸首。根据FDA目前的标准，如果在24小时内清除多达25%的红细胞，从而向单核-巨噬细胞系统提供大量的铁，则临床上可以接受输血单位储存的红细胞(RBC)。这一建议的中心假设是，铁在吞噬细胞内和细胞外作为血浆非转铁蛋白结合铁(NTBI)发挥作用，是造成与储存的红细胞输注相关的不良反应的原因。为了实现我们的目标，我们将使用特征良好的小鼠输血和脓毒症模型。这项研究有三个具体目标：目的1：验证细胞内铁水平升高的促氧化作用是输注较老储存的红细胞后观察到的促炎状态的假说。目的#2：验证一个假设，即储存的较老红细胞的急性清除改变了辅助性T细胞(TH)对TH17细胞的分化。目的#3：在单细菌感染和多菌败血症模型中，验证NTBI在旧储存的红细胞急性清除后释放会增加感染严重程度的假设。因此，这项建议将在目标1中定义铁侮辱的机制，在目标2中表征对这种侮辱的免疫反应，并在目标3中研究这种侮辱的临床后果。从这个项目中获得的见解将指导未来评估人类输血医学新治疗方法的临床前研究。该项目连同一个完善的职业发展计划，包括四位杰出的导师和顾问，将为申请者提供免疫学和铁生物方面的培训工具，这将使他的研究生涯发展为一名独立的调查人员。

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.