Immunobiology of Transfusion

输血免疫生物学

• 批准号: 10192789
• 负责人: JAMES C. ZIMRING
• 金额: $ 246.56万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192789
• 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.

项目摘要 这是计划项目赠款（P01）的应用 对红细胞（RBC）输血的免疫复杂的细胞和分子机制。虽然经常 救生，输血也可能导致RBC同种免疫，抗RBC同抗体最终可以 导致胎儿和新生儿的溶血输血反应延迟和/或溶血性疾病， 导致发病率和在某些情况下死亡。此外，大量人类流行病学数据 表明RBC上的同种抗原代表具有受体反应模式的独特免疫抑制剂 这与更好的研究局面有很大不同。目前，我们对如何理解 输血的RBC驱动免疫反应（或不这样做）仍然有限。在这里，我们提出了一个广泛的 旨在采用创新和尖端的“输血免疫生物学”的协作计划题为“免疫生物学” 临床前模型和免疫学工具，结合人类研究，以实验确定 调节RBC同种异体免疫的分子和细胞途径。拟议的计划由四个 项目和两个核心。首席研究员和项目负责人都是正式的身体科学家 免疫学的基础科学培训以及临床关注输血医学。而且， 这是一个新程序的应用程序，它建立在该应用程序的十年协作工作的基础上 研究人员为协同合作提供了历史基础。项目1将调查机制 RBC的抗体调节同种免疫，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，分子研究 IgG亚型和FCR生物学的作用。项目2将重点关注边缘区B的作用 RBC中的细胞同种免疫，研究人类志愿者和镰状细胞疾病的患者。项目3 将研究哪些先天免疫接收器被输血的RBC激活，并且需要功能 对于依赖T细胞的RBC同种抗体产生，重点是MyD88驱动的细胞反应， 识别类似受体的收费和细胞因子网络。项目4将侧重于 使用临床前模型并研究镰状患者 细胞疾病。有两个辅助核心。核心A（管理核心）将监督和协调 该计划的行政，科学和财政运营以及为所有人提供生物统计学支持 项目。核心B（小鼠血液中心核心）将建立一个经济有效，集中式，质量控制的，并且 标准化的血液收集/加工中心，用于生成鼠标RBC的单位 项目。总的来说，该计划将对如何产生基本的机械和转化见解 输血会导致RBC同种异体免疫化，为开发新的治疗干预提供了合理的基础 总体而言，还会产生对免疫学的新了解。

项目成果

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction.

• DOI: 10.21037/aob-2020-scd-01
• 发表时间: 2020-12-01
• 期刊: Annals of blood
• 作者: Hendrickson, Jeanne E

Innate and Adaptive Immunity to Transfused Allogeneic RBCs in Mice Requires MyD88.

• DOI: 10.4049/jimmunol.2100784
• 发表时间: 2022-02-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Soldatenko A;Hoyt LR;Xu L;Calabro S;Lewis SM;Gallman AE;Hudson KE;Stowell SR;Luckey CJ;Zimring JC;Liu D;Santhanakrishnan M;Hendrickson JE;Eisenbarth SC
• 通讯作者: Eisenbarth SC

Identification of multiple genetic loci associated with red blood cell alloimmunization in mice.

• DOI: 10.3324/haematol.2022.281767
• 发表时间: 2023-03-01
• 期刊: HAEMATOLOGICA
• 影响因子: 10.1
• 作者: Jash, Arijita;Howie, Heather L.;Hay, Ariel M.;Luckey, Chance John;Hudson, Krystalyn E.;Thomson, Peter C.;Ratcliffe, Sarah J.;Smolkin, Mark;Zimring, James C.
• 通讯作者: Zimring, James C.