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

1 型干扰素在调节输注红细胞同种免疫反应中的作用

• 批准号: 10194579
• 负责人: David R Gibb
• 金额: $ 16.41万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194579
• 关键词: Alloantigen; Allogenic; Alloimmunization; American; Anemia; Antibodies; Antibody Formation; Antigens; Autoimmune; Autoimmune Diseases; B Cell Proliferation; B cell differentiation; B-Cell Development; B-Lymphocytes; Biometry; Cell Culture Techniques; Cell physiology; Cells; Cellular Structures; Data; Defect; Dendritic Cells; Development Plans; Disease; Environmental Risk Factor; Erythrocyte Transfusion; Erythrocytes; Event; Exposure to; Fetal Erythroblastosis; Flow Cytometry; Frequencies; Genes; Genetic; Goals; High-Throughput RNA Sequencing; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunohistochemistry; Immunologics; Immunology; Individual; Inflammation; Inflammatory; Interferon-alpha; Interferons; International; Intervention; Isoantibodies; Laboratories; Lead; Life; Location; Lymphoid Tissue; Measures; Mediating; Medicine; Mentors; Mentorship; Microscopic; Molecular; Morbidity - disease rate; Morphology; Mus; National Heart, Lung, and Blood Institute; Natural Immunity; Pathology; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Physicians; Plasma Cells; Postdoctoral Fellow; Procedures; Production; Reaction; Receptor Signaling; Regulation; Reporter; Reporting; Research; Research Personnel; Research Priority; Risk; Role; Safety; Savings; Scientist; Serum; Signal Pathway; Signal Transduction; Source; Spleen; State Hospitals; Stimulus; Structure of germinal center of lymph node; Testing; Training; Transcript; Transfusion; Translating; United States; Viremia; Virus Diseases; Wild Type Mouse; antiviral immunity; blood product; career; career development; cytokine; differential expression; experience; high throughput analysis; immunohematology; improved; in vivo; innate immune mechanisms; medical schools; mortality; mouse model; protein expression; receptor; receptor expression; response; skills; transcriptome; transcriptome sequencing; transfusion medicine

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.

抽象的： 每年约有500万美国人输血，红细胞（RBC）输血最多 在美国医院进行的常见程序。 RBC输血将接收者暴露于数百个 捐赠者和接受者之间不匹配的非ABO抗原。这种暴露会导致生产 抗原特异性同种抗体，这可能引起潜在的致命溶血输血反应并限制 兼容血液产品的可用性，导致贫血相关的发病率和死亡率。目前，那里 不能预测哪些接受者的同种异体风险升高。处于风险的识别 患者将允许采取干预措施来抑制同种免疫及其有害作用。那，识别 确定哪些人会产生RBC同种异体反应的因素已被认为是 NHLBI的输血医学的研究优先级。一个因素之一是 输血接受者。最近的研究报告说 传播病毒感染或炎症性疾病，包括多种自身免疫性疾病。但是， 这种关联的基础机制，包括关键炎性细胞因子的作用，是 理解不佳。鉴于该1型干扰素（IFNα/β）调节抗病毒免疫学和自身免疫性病理学， 我们假设IFNα/β信号传导调节了对RBC抗原的同种异体免疫反应。初步数据 表明小鼠同种免疫需要IFNα/β的产生和信号，特别是在B细胞中。 我们使用输血模型，旨在确定输血诱导的IFNα/β的基础机制 在RBC同种异体释放期间，生产（AIM 1）和B细胞对IFNα/β信号的反应（AIM 2）。调查结果会 为过去观察到炎症诱导的同种异体免疫性提供了潜在的机械基础。 此外，结果可以确定实验室测试的潜在目标，以改善预测 同种免疫。候选人是实验室医学博士后研究员。他提议获得指导 研究经验和职业发展培训是输血医学的身体科学家。这 项目将提供将先天免疫机制应用于RBC AlloMune的调节的经验 回答。在输血领导者的心态下，将在耶鲁医学院进行培训 医学和先天免疫。候选人将发展实验和分析技能，包括 淋巴组织的微观分析，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。他将完成一项包括课程的职业发展计划 在炎症，生物统计学和翻译免疫学中。他的职业指导将由他的职业发展 参与免疫血液学研究的地方和国际协会。这样的培训将是 助长申请人的目标是将免疫学发现产生和转化为改进的输血 作为独立调查员的安全。