The role of type 1 interferon in regulating alloimmune responses to transfused red blood cells

摘要： 每年约有500万美国人输血，红细胞（RBC）输血是最常见的。 在美国医院进行的常见手术。红细胞输血使接受者暴露于数百种 非ABO抗原在供体和受体之间不匹配。这种接触可能会导致生产 抗原特异性同种抗体，可导致潜在致命的溶血性输血反应， 相容性血液制品的可用性，导致贫血相关的发病率和死亡率。目前 并不能预测哪些接受者有更高的同种免疫风险。风险识别 患者将允许干预以抑制同种免疫及其有害影响。因此，识别 决定哪些个体将产生RBC同种免疫应答的因素已被认为是一个重要的因素。 NHLBI的输血医学研究优先权。一个促成因素是炎症状态的 输血接受者最近的研究报道了在患有糖尿病的患者中同种免疫的频率增加。 播散性病毒感染或炎性疾病，包括多种自身免疫性疾病。但 这种关联的分子机制，包括关键炎症细胞因子的作用， 不太了解。考虑到1型干扰素（IFNα/β）调节抗病毒免疫和自身免疫病理， 我们假设IFNα/β信号传导调节对RBC抗原的同种免疫应答。初步数据 表明IFNα/β产生和信号传导，特别是在B细胞中，是小鼠同种免疫所必需的。 利用小鼠输血模型，我们的目的是确定输血诱导IFNα/β的机制， 产生（目的1）和RBC同种免疫期间B细胞对IFNα/β信号传导的应答（目的2）。发现将 为过去炎症诱导的同种异体免疫的观察提供了潜在的机制基础。在 此外，结果可以确定实验室测试的潜在目标，这些目标可以改善对疾病的预测。 同种免疫候选人是实验室医学的博士后研究员。他打算接受 研究经验和职业发展培训作为一个医生，科学家在输血医学。的 该项目将提供应用先天免疫机制调节红细胞同种免疫的经验 应答培训将在耶鲁医学院进行，由输血领域的领导者指导。 医学和先天免疫。候选人将发展实验和分析技能，包括 淋巴组织的显微镜分析，体内B细胞过程的定量，以及采集和分析 高通量RNA测序数据。他将完成包括课程在内的职业发展计划 在炎症、生物统计学和转化免疫学方面。他的职业方向将由他的 参与当地和国际免疫血液学研究协会。这种培训将是 有助于申请人产生免疫学发现并将其转化为改善的输血的目标 作为一名独立的调查员。

Abstract: With approximately 5 million Americans transfused per year, red blood cell (RBC) transfusion is the most common procedure performed in United States hospitals. RBC transfusion exposes recipients to hundreds of non-ABO antigens that are not matched between donors and recipients. This exposure can lead to production of antigen-specific alloantibodies, which can cause potentially fatal hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Currently, there are no means to predict which recipients have an elevated risk of alloimmunization. Identification of at-risk patients would allow for interventions to inhibit alloimmunization and its detrimental effects. Thus, identifying factors that determine which individuals will develop RBC alloimmune responses has been recognized as a research priority in transfusion medicine by the NHLBI. One contributing factor is the inflammatory state of the transfusion recipient. Recent studies have reported an increased frequency of alloimmunization in patients with disseminated viral infections or inflammatory diseases, including multiple autoimmune diseases. However, the molecular mechanisms underlying this association, including the role of critical inflammatory cytokines, are poorly understood. Given that type 1 interferons (IFNα/β) regulate antiviral immunity and autoimmune pathology, we hypothesize that IFNα/β signaling regulates alloimmune responses to RBC antigens. Preliminary data indicate that IFNα/β production and signaling, specifically in B cells, is required for alloimmunization in mice. Using a murine model of transfusion, we aim to identify mechanisms underlying transfusion-induced IFNα/β production (Aim 1) and B cell responses to IFNα/β signaling during RBC alloimmunization (Aim 2). Findings will provide a potential mechanistic basis for past observations of inflammation-induced alloimmunization. In addition, results may identify potential targets of laboratory tests that could improve prediction of alloimmunization. The candidate is a post-doctoral fellow in Laboratory Medicine. He proposes to gain mentored research experience and career development training as a physician-scientist in Transfusion Medicine. The project will provide experience in applying innate immune mechanisms to regulation of RBC alloimmune responses. Training will be conducted at Yale School of Medicine under the mentorship of leaders in Transfusion Medicine and innate immunity. The candidate will develop experimental and analytical skills, including microscopic analysis of lymphoid tissue, quantification of B cell processes in vivo, and acquisition and analysis of high-throughput RNA sequencing data. He will complete a career development plan that includes coursework in inflammation, biostatistics, and translational immunology. His career directions will be shaped by his participation in local and international associations of immuno-hematology research. Such training will be instrumental to the applicant's goal of generating and translating immunologic findings into improved transfusion safety as an independent investigator.