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 万美国人接受输血，其中红细胞 (RBC) 输血是最常见的输血方式。 在美国医院进行的常见手术。红细胞输血使受血者接触到数百种 供者和受者之间不匹配的非 ABO 抗原。这种暴露可能会导致生产 抗原特异性同种抗体，可能导致潜在致命的溶血性​​输血反应并限制 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，有 没有办法预测哪些接受者的同种免疫风险较高。识别高危人群 患者会允许采取干预措施来抑制同种免疫及其有害影响。因此，识别 决定哪些个体会产生红细胞同种免疫反应的因素已被认为是 NHLBI 优先研究输血医学。影响因素之一是炎症状态 输血接受者。最近的研究报告称，患有以下疾病的患者的同种免疫接种频率有所增加 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， 这种关联的分子机制，包括关键炎症细胞因子的作用，是 不太了解。鉴于 1 型干扰素 (IFNα/β) 调节抗病毒免疫和自身免疫病理学， 我们假设 IFNα/β 信号传导调节对红细胞抗原的同种免疫反应。初步数据 表明 IFNα/β 的产生和信号传导（特别是在 B 细胞中）是小鼠同种免疫所需的。 使用小鼠输血模型，我们的目的是确定输血诱导的 IFNα/β 的机制 红细胞同种免疫过程中 IFNα/β 信号传导的产生（目标 1）和 B 细胞反应（目标 2）。调查结果将 为过去对炎症诱导的同种免疫的观察提供了潜在的机制基础。在 此外，结果可能会确定实验室测试的潜在目标，从而改善对疾病的预测 同种免疫。该候选人是检验医学博士后研究员。他提议获得指导 作为输血医学医师科学家的研究经验和职业发展培训。这 项目将提供应用先天免疫机制来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输血领域领导者的指导下进行 医学和先天免疫。候选人将培养实验和分析技能，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RNA测序数据。他将完成一份职业发展计划，其中包括课程作业 炎症、生物统计学和转化免疫学。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。此类培训将 有助于申请人实现免疫学发现并将其转化为改进输血的目标 作为独立调查员的安全。