Mechanisms underlying the harmful effects of stored red blood cell transfusions

储存红细胞输注有害影响的机制

• 批准号: 8442306
• 负责人: Eldad Arie Hod
• 金额: $ 13.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442306
• 关键词: Acute; Address; Adverse effects; Anemia; Autoimmune hemolytic anemia; Binding; Biology; Blood Transfusion; Blood donor; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Clinical; Data; Development Plans; Disease; Dose; Endotoxins; Erythrocyte Transfusion; Erythrocytes; Foundations; Future; Glucosephosphate Dehydrogenase Deficiency; Goals; Growth; Helper-Inducer T-Lymphocyte; Hemoglobin; Hemolysis; Hour; Human; Human Volunteers; Immune response; Immunology; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Intensive Care Units; Iron; Late Effects; Life; Medicine; Mentors; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Patients; Phagocytes; Plasma; Postoperative Period; Reactive Oxygen Species; Research; Research Personnel; Risk; Sepsis; Serum iron level result; Severities; System; Testing; Training; Transferrin; Transfusion; Trauma; bactericide; career; career development; cytokine; design; effective therapy; improved; insight; macrophage; meetings; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; preclinical study; public health relevance; research study; senescence; total measurement Bilirubin; volunteer

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.

描述（由申请人提供）：本研究旨在确定由于铁的急性递送到单核-巨噬细胞系统而导致的储存红细胞输血的不良反应的程度。虽然输血对治疗症状性贫血是有效的，但越来越多的证据表明，输血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强烈表明，情况确实如此，铁最有可能是产生这些不利影响的罪魁祸首。根据目前的FDA标准，如果在24小时内25%的红细胞被清除，那么一个单位的红细胞（RBC）在临床上是可以接受的，从而向单核-巨噬细胞系统输送大量的铁。该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），负责与储存红细胞输血相关的不良反应。为了实现我们的目标，我们将使用具有良好特征的输血和败血症小鼠模型。本研究有三个具体目的：目的1：验证细胞内铁水平增加的促氧化作用是在输注较老的、储存的红细胞后观察到的促炎症状态的原因。目的2：验证急性清除储存较老的红细胞会改变辅助性T细胞（TH）向TH17细胞分化的假设。目的3：验证在单核细菌感染和多微生物脓毒症模型中，急性清除储存的老红细胞后释放的NTBI增加感染严重程度的假设。因此，本提案将在Aim #1中定义铁损伤的机制，在Aim #2中表征对这种损伤的免疫反应，并在Aim #3中研究这种损伤的临床后果。从这个项目中获得的见解将指导未来的临床前研究，评估人类输血医学的新治疗方法。本项目将为申请人提供完善的职业发展规划，包括四位杰出的导师和顾问，为申请人提供免疫学和铁生物学方面的培训工具，将其研究生涯提升到独立研究者的水平。