Immunobiology of Transfusion

输血免疫生物学

• 批准号: 10018077
• 负责人: JAMES C. ZIMRING
• 金额: $ 246.85万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018077
• 关键词: Affect; Alloantigen; Alloimmunization; American; Animal Model; Antibodies; B-Lymphocytes; Back; Basic Science; Biology; Biometry; Blood; Cells; Cellular biology; Clinical; Clinical Data; Collaborations; Collection; Cytokine Network Pathway; Data; Disease; Dissection; Erythrocyte Transfusion; Erythrocytes; Fetus; Generations; Goals; Grant; Healthcare; Helper-Inducer T-Lymphocyte; Human; Human Volunteers; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunization; Immunobiology; Immunoglobulin G; Immunologic Receptors; Immunologics; Immunology; Inpatients; Investigation; Isoantibodies; Lead; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Newborn Infant; Pathway interactions; Patient Care; Patients; Pattern; Peer Review; Physicians; Pre-Clinical Model; Principal Investigator; Procedures; Production; Productivity; Program Research Project Grants; Prophylactic treatment; Publications; Publishing; Reaction; Regulation; Reporting; Research Personnel; Role; Scientist; Series; Sickle Cell Anemia; Signal Pathway; Standardization; Stimulus; Structure; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Toll-like receptors; Training; Transfusion; Work; acute chest syndrome; base; bench to bedside; clinically relevant; cost effective; cytokine; epidemiologic data; immune activation; immune function; immunoregulation; innovation; insight; mortality; mouse model; multidisciplinary; novel; novel therapeutic intervention; operation; pre-clinical; prevent; programs; response; success; therapy development; tool; transfusion medicine; translational scientist

Project Summary This is an application of a Program Project Grant (P01) for a coordinated, multi-disciplinary investigation of the cellular and molecular mechanisms of immune responses to red blood cell (RBC) transfusion. Though often lifesaving, transfusions can also lead to RBC alloimmunization, whereby anti-RBC alloantibodies can ultimately result in both Delayed Hemolytic Transfusion Reactions and/or Hemolytic Disease of the Fetus and Newborn, leading to morbidity and in some cases mortality. In addition, large quantities of human epidemiological data indicate that alloantigens on RBCs represent a distinct immune stimulus with a pattern of recipient responses that differs substantially from better studied scenarios of immunization. Currently, our understanding of how transfused RBCs drive immune responses (or fail to do so) remains limited. Herein we propose an extensive collaborative program entitled "Immunobiology of Transfusion" aimed at employing innovative and cutting edge pre-clinical models and immunological tools, combined with human studies, to experimentally determine the molecular and cellular pathways that regulate RBC alloimmunization. The proposed program consists of four projects and two cores. The principal investigator and project leaders are all physician-scientists with formal basic science training in immunology and also with a clinical focus on transfusion medicine. Moreover, while this is an application for a new program, it builds upon a decade of collaborative work by the applicant investigators, providing a historical basis for synergistic collaboration. Project 1 will investigate mechanisms by which antibodies to RBCs regulate alloimmunization as a model to study anti-RhD immune prophylaxis. Tested hypotheses include cellular mechanisms of anti-RBC immunoregulation, molecular investigations of the role of IgG subtypes, and FcR biology. Project 2 will focus on investigation of the role of marginal zone B cells in RBC alloimmunization, studying both human volunteers and patients with sickle cell disease. Project 3 will investigate which innate immune receptors are activated by transfused RBCs and are functionally required for T cell dependent RBC alloantibody generation with a focus on MyD88-driven cellular responses, identification of Toll like receptors involved, and cytokine networks. Project 4 will focus on the biology of follicular helper T cells and specific cytokine circuits, using pre-clinical models and studying patients with sickle cell disease. There are two supporting cores. Core A (administrative core) will oversee and coordinate the administrative, scientific, and fiscal operation of the program as well as providing biostatistics support to all projects. Core B (mouse blood center core) will set up a cost effective, centralized, quality controlled and standardized blood collection/processing center for generating units of mouse RBCs that will be used by all 4 projects. Collectively, this program will yield fundamental mechanistic and translational insights into how transfusion leads to RBC alloimmunization, provide a rational basis to develop new therapeutic interventions and also generate novel understanding of immunology, in general.

项目概要 这是一项计划项目补助金 (P01) 的申请，旨在对以下问题进行协调一致的多学科调查： 红细胞（RBC）输注免疫反应的细胞和分子机制。虽然经常 挽救生命，输血还可以导致红细胞同种免疫，从而抗红细胞同种抗体最终可以 导致胎儿和新生儿的迟发性溶血性输血反应和/或溶血病， 导致发病，在某些情况下甚至导致死亡。此外，大量的人类流行病学数据 表明红细胞上的同种异体抗原代表了一种独特的免疫刺激，具有受体反应的模式 这与经过更好研究的免疫方案有很大不同。目前，我们对如何 输入的红细胞驱动免疫反应（或未能这样做）仍然有限。在此，我们提出了广泛的 题为“输血免疫生物学”的合作计划旨在采用创新和尖端技术 临床前模型和免疫学工具，结合人体研究，通过实验确定 调节红细胞同种免疫的分子和细胞途径。拟议的计划包括四个 项目和两个核心。主要研究者和项目负责人都是具有正式资格的医师科学家 免疫学基础科学培训以及输血医学临床重点。此外，虽然 这是一个新项目的申请，它建立在申请人十年的合作工作之上 调查人员，为协同合作提供历史基础。项目1将研究机制 红细胞抗体通过调节同种免疫作为研究抗 RhD 免疫预防的模型。 经检验的假设包括抗红细胞免疫调节的细胞机制、 IgG 亚型的作用和 FcR 生物学。项目2将重点研究边缘区B的作用 红细胞同种免疫中的细胞，研究人类志愿者和镰状细胞病患者。项目3 将研究哪些先天免疫受体被输注的红细胞激活并且是功能所需的 用于 T 细胞依赖性红细胞同种抗体生成，重点关注 MyD88 驱动的细胞反应， 鉴定所涉及的 Toll 样受体和细胞因子网络。项目4将重点关注生物学 滤泡辅助 T 细胞和特定细胞因子回路，使用临床前模型并研究镰状细胞病患者 细胞疾病。有两个支撑核心。核心 A（行政核心）将监督和协调 该计划的行政、科学和财政运作，以及向所有人提供生物统计支持 项目。核心B（小鼠血液中心核心）将建立一个具有成本效益、集中化、质量控制和 标准化血液采集/处理中心，用于生成小鼠红细胞单位，供所有 4 个单位使用 项目。总的来说，该计划将产生基本的机制和转化见解，以了解如何 输血导致红细胞同种免疫，为开发新的治疗干预措施提供合理基础 总体而言，还可以产生对免疫学的新理解。