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.

项目总结