Cyokine control of red blood cell alloimmunization

红细胞同种免疫的细胞因子控制

• 批准号: 9214994
• 负责人: CHANCE MARION JOHN LUCKEY
• 金额: $ 51.91万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214994
• 关键词: Accounting; Alloantigen; Alloimmunization; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; BCL6 gene; Biochemical Genetics; Biological Models; Biological Response Modifiers; Blocking Antibodies; Bone Marrow; Cell Differentiation process; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Clinical Research; Cytokine Signaling; Data; Detection; Diagnostic; Erythrocyte Transfusion; Erythrocytes; Exposure to; Funding; Generations; Genetic; Helper-Inducer T-Lymphocyte; Hematological Disease; Human; Immune; Immunization; Immunologics; Interleukin-6; Isoantibodies; Lead; Life; Maintenance; Mediating; Medicine; Memory; Memory B-Lymphocyte; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; National Heart, Lung, and Blood Institute; Nature; Patients; Plasma Cells; Play; Prevention; Production; Reaction; Resources; Risk; Role; STAT3 gene; Savings; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Transfusion; Treatment Efficacy; Vaccination; Work; cellular targeting; clinical development; cytokine; differentiated B cell; experimental study; falls; high risk; interest; mortality; mouse model; patient population; plasma cell differentiation; pre-clinical; prevent; response; vaccination strategy

Summary. Red blood cell (RBC) alloimmunization remains a significant clinical problem in transfusion medicine, particularly among those patients who require chronic transfusions. For those who are unfortunate enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can be both time and resource intensive. In rare cases, this can result in an inability to locate an otherwise life-saving therapy. RBC alloantibodies are also responsible for hemolytic transfusion reactions (HTRs), causing substantial morbidity and occasional mortality. HTRs result from two important immunological phenomena. The first is the uniquely evanescent nature of RBC antibodies, whose rapid disappearance leads to false negative screens in alloimmunized patients. The second is the recall antibody response elicited by re-exposure to antigen via subsequent transfusion, where the rapid and robust increase in circulating antibodies drive HTRs. Despite the significant clinical consequences of these phenomena, our understanding of the fundamental molecular and cellular mechanisms regulating anti-RBC antibody generation, maintenance and recall is remarkably limited. Accordingly, there are no effective therapeutic interventions available to alloimmunized patients other than antigen avoidance. Our previous work has identified IL-6 as a key cytokine signal that regulates both the initial alloimmunization response to RBCs as well as early T follicular helper cell (TFH) differentiation. We are now interested in extending our findings to investigate the role of IL-6 signals in controlling RBC alloantibody evanescence and recall responses. Given the pleomorphic nature of IL-6 signaling, we are interested in determining both the cellular targets (B vs. T cell), downstream signaling molecules (STAT3), and cellular consequences (short-lived plasma cell, long-lived plasma cell, memory B cell and memory TFH cell differentiation) regulated by IL-6 and required for RBC alloimmunization. Accordingly, we will employ cutting-edge conditional genetic mouse mutants of IL-6R, STAT3, and BCL6 to directly compare antibody and cellular responses to two different mouse models of RBC alloimmunization as well as standard vaccination approaches. In so doing, we will better understand how the fundamental cellular and molecular immune regulators of RBC alloimmunization vary for different RBC antigen systems, and also how they compare to traditional immune stimulation. Furthermore, we will develop a pre-clinical mouse model system to determine the therapeutic efficacy of targeting the IL-6/IL-6R signaling pathway for the prevention and/or treatment of RBC alloimmunization, serving as key data for the subsequent consideration of IL-6R antibody blocking therapies (such as Tocilizumab) in select, high-risk alloimmunized patients.

总结。红细胞异体免疫仍然是输血中的一个重要临床问题