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，其中以红细胞输血最多。 在美国医院中进行的常见程序。RBC输血使接受者暴露于数百例 供者和受者之间不匹配的非ABO抗原。这种接触可能会导致生产 抗原特异性同种异体抗体，这可能导致潜在的致命溶血性输血反应和限制 可获得相容的血液产品，导致贫血相关发病率和死亡率。目前，有 无法预测哪些受者的异基因免疫风险较高。风险中的识别 患者将允许采取干预措施，以抑制同种异体免疫及其有害影响。因此，识别 决定哪些人会产生RBC同种免疫反应的因素被认为是一种 NHLBI在输血医学方面的研究重点。其中一个因素是血管的炎症状态 输血接受者。最近的研究报告说，在慢性阻塞性肺疾病患者中，异基因免疫的频率增加 播散性病毒感染或炎症性疾病，包括多种自身免疫性疾病。然而， 这种联系背后的分子机制，包括关键的炎症细胞因子的作用，是 人们对此知之甚少。鉴于1型干扰素(干扰素α/β)调节抗病毒免疫和自身免疫病理， 我们假设干扰素α/β信号调节对红细胞抗原的同种异体免疫反应。初步数据 提示同种异体免疫需要干扰素α/β的产生和信号，特别是在B细胞中。 利用小鼠输血模型，我们的目标是确定输血诱导干扰素α/β的机制。 在红细胞同种异体免疫期间产生(目标1)和B细胞对干扰素α/β信号的反应(目标2)。调查结果将 为过去对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……里面 此外，结果可能确定可能改善预测的实验室测试的潜在目标 同种异体免疫。候选人是实验室医学博士后研究员。他提议得到指导 作为输血内科医生-科学家的研究经验和职业发展培训。这个 该项目将提供将先天免疫机制应用于调节红细胞同种免疫的经验 回应。培训将在耶鲁大学医学院进行，由输血领域的领导人指导 医学和先天免疫力。应聘者将发展实验和分析技能，包括 淋巴组织的显微分析，体内B细胞过程的量化，以及采集和分析 高通量的RNA测序数据。他将完成一项职业发展计划，其中包括课程 在炎症、生物统计学和翻译免疫学方面。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。这样的培训将是 有助于申请人产生免疫学发现并将其转化为改进的输血 作为一名独立调查人员的安全。

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.