Immunobiology of Transfusion

输血免疫生物学

• 批准号: 9360036
• 负责人: JAMES C. ZIMRING
• 金额: $ 237.4万
• 依托单位: BLOODWORKS
• 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/9360036
• 关键词: Affect; Alloantigen; Alloimmunization; Alpha Cell; American; Animal Model; Antibodies; B-Lymphocytes; Back; Basic Science; Biology; Biometry; Blood; CD4 Positive T Lymphocytes; 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; Medicine; 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; Quality Control; 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; 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.

项目摘要 这是一份计划项目补助金（P01）的申请，用于协调的、多学科的调查。 红细胞（RBC）输注免疫应答的细胞和分子机制。虽然常常 输血可以挽救生命，也可以导致红细胞同种异体免疫，因此抗红细胞同种异体抗体最终可以 导致胎儿和新生儿的迟发性溶血性输血反应和/或溶血性疾病， 从而导致发病，在某些情况下导致死亡。此外，大量的人类流行病学数据 表明RBC上同种异体抗原代表了具有受体应答模式的独特免疫刺激 这与更好研究的免疫方案有很大不同。目前，我们对 输注的红细胞驱动免疫应答（或不能这样做）仍然有限。在此，我们提出了一个广泛的 一项名为“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，以实验方式确定 调节RBC同种免疫的分子和细胞途径。拟议方案包括四个 项目和两个核心。主要研究者和项目负责人都是医生科学家， 免疫学的基础科学培训，以及输血医学的临床重点。而且，尽管 这是一个新项目的申请，它建立在申请人十年合作的基础上 研究人员，为协同合作提供了历史基础。项目1将调查机制 红细胞抗体调节同种异体免疫，作为研究抗RhD免疫预防的模型。 测试的假设包括抗RBC免疫调节的细胞机制， IgG亚型的作用和Fc γ R生物学。项目2将侧重于调查边缘区B的作用 红细胞同种免疫中的红细胞，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，并在功能上需要 对于T细胞依赖性RBC同种抗体产生，重点是MyD 88驱动的细胞应答， 鉴定所涉及的Toll样受体和细胞因子网络。项目4将侧重于生物学 滤泡辅助性T细胞和特异性细胞因子回路，使用临床前模型并研究镰状细胞病患者 细胞疾病有两个支持核心。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，以及为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的、集中的、质量受控的 标准化的血液采集/处理中心，用于生成所有4个单位的小鼠RBC 项目总的来说，这个计划将产生基本的机械和翻译的见解，如何 输血导致红细胞同种异体免疫，为开发新的治疗干预措施提供合理依据 也产生了对免疫学的新的理解。