Molecular determinants of anti-RBC alloantibody evanescence

抗红细胞同种抗体消失的分子决定因素

基本信息

批准号：
10687424
负责人：
CHANCE MARION JOHN LUCKEY
金额：
$ 79.83万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687424
关键词：
Affinity Allogenic Alloimmunization Antibodies Antibody Affinity Antibody Formation Antibody Response Antigen Presentation Antigen-Presenting Cells Antigens Apoptotic Automobile Driving B cell differentiation B-Lymphocytes Biological Response Modifiers Blood Blood Banks CD4 Positive T Lymphocytes Cell Differentiation process Cells Cessation of life Chronic Chronic Care Clinical Complication Coupled Data Dendritic Cells Dendritic cell activation Dependence Detection Development Diagnostic Drops Erythrocyte Transfusion Erythrocytes Event Future Generations Helper-Inducer T-Lymphocyte Immune Immune response Immunoglobulin Somatic Hypermutation Inflammatory Injury Innate Immune Response Innate Immune System Interleukin-10 Interleukin-4 Isoantibodies Lead Life Lipids Malaria Modeling Molecular Molecular Target Morbidity - disease rate Patients Phenotype Plasma Cells Plasmablast Platelet Activating Factor Process Production Publishing Reaction Risk Serine Sickle Cell Anemia Signal Transduction Structure of germinal center of lymph node T-Lymphocyte TNFSF4 gene Testing Therapeutic Therapeutic Intervention Time Transfusion Vaccination Virus Diseases clinical development differential expression falls hazard high risk malaria infection mortality mouse model novel novel therapeutic intervention patient response response therapeutically effective

项目摘要

Summary. For patients who require chronic transfusion, the generation of antibodies to red blood cell (RBC) antigens can be a major clinical problem. Anti-RBC antibodies often make finding compatible blood difficult for these patients, which is particularly unfortunate since these RBC transfusions are often lifesaving. A major complication arises when these anti-RBC alloantibodies disappear before detection in the blood bank, a process referred to as evanescence. Patients whose antibodies have disappeared can unknowingly receive a second transfusion of incompatible blood. This incompatible transfusion can induce a life-threatening event called delayed hemolytic transfusion reaction. Anti-RBC evanescence therefore directly leads to delayed hemolytic transfusion reactions, which are a major cause of injury and death in chronically transfused patients. This is a particularly serious problem for patients with sickle cell disease, who often require frequent transfusions and have high rates of evanescent antibodies. Despite its clinical importance, the molecular factors that lead to anti-RBC alloantibody evanescence are completely unknown. Accordingly, there are no effective therapeutic interventions available to alloimmunized patients other than antigen avoidance. We have recently made the novel finding that the HOD mouse model of red blood cell (RBC) alloimmunization recapitulates many of the key clinical features seen in chronically transfused patients. Specifically, we have shown that HOD RBC transfusion leads to the preferential generation of low-affinity, rapidly evanescent anti- RBC alloantibodies at the expense of high-affinity, persistent antibodies. Herein we propose to use this mouse model to investigate why RBC transfusion leads to rapidly evanescent antibodies rather than long-lived ones. Our central hypothesis is that RBC presentation of antigens directly alters the innate immune responses of recipients, driving the differentiation of CD4+ T cells into helper cells which are unable to sustain long-lived interactions with B cells. We hypothesize that though these T cells can drive extrafollicular antibody responses that produce low-affinity, short-lived antibodies, they are blocked in their ability to drive germinal center responses that allow for somatic hypermutation, antibody affinity maturation, and long-lived antibody producing plasma cells. By better understanding how the fundamental cellular and molecular immune regulators of anti-RBC alloantibodies are regulated over time, we hope to discover novel molecular targets that can serve as potential future therapeutics for those patients who are at high risk from the complications of RBC alloimmunization.

概括。对于需要长期输血的患者，红细胞（RBC）抗体的产生抗原可能是一个主要的临床问题。抗红细胞抗体通常使寻找相容的血液变得困难对于这些患者来说，这是特别不幸的，因为这些红细胞输注通常可以挽救生命。一个专业当这些抗红细胞同种抗体在血库检测之前消失时，就会出现并发症，过程称为消逝。抗体消失的患者可以在不知不觉中接受第二次输注不相容的血液。这种不相容的输血可能会引发危及生命的事件称为迟发型溶血性输血反应。因此，抗红细胞消失直接导致延迟溶血性输血反应是长期输血患者受伤和死亡的主要原因。对于镰状细胞病患者来说，这是一个特别严重的问题，他们经常需要频繁输血并且消失抗体的发生率很高。尽管其临床重要性，分子导致抗红细胞同种抗体消失的因素尚不清楚。据此，不存在除了抗原回避之外，同种免疫患者还可以采取有效的治疗干预措施。我们有近期取得红细胞（RBC）同种免疫HOD小鼠模型的新发现概括了长期输血患者的许多关键临床特征。具体来说，我们有表明 HOD RBC 输注会导致优先产生低亲和力、快速消失的抗- 红细胞同种抗体以高亲和力、持久性抗体为代价。这里我们建议使用这款鼠标该模型旨在研究为什么红细胞输注会导致抗体快速消失而不是长期存在。我们的中心假设是红细胞抗原的呈递直接改变了先天免疫反应受体，驱动 CD4+ T 细胞分化为无法维持长寿的辅助细胞与 B 细胞的相互作用。我们假设这些 T 细胞可以驱动滤泡外抗体反应产生低亲和力、寿命短的抗体，它们驱动生发中心的能力被阻断允许体细胞超突变、抗体亲和力成熟和长寿命抗体的反应产生浆细胞。通过更好地了解基本的细胞和分子免疫如何抗红细胞同种抗体的调节因子随着时间的推移而受到调节，我们希望发现新的分子靶点对于那些并发症高风险的患者来说，这可以作为未来潜在的治疗方法红细胞同种免疫。