Molecular determinants of anti-RBC alloantibody evanescence

抗红细胞同种抗体消失的分子决定因素

• 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
• 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

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.

摘要对于需要长期输血的患者，红细胞（RBC）抗体的产生 抗原可能是主要的临床问题。抗红细胞抗体通常使寻找相容血液变得困难 对于这些病人来说，这是特别不幸的，因为这些红细胞输注通常可以挽救生命。一个主要 当这些抗RBC同种抗体在血库中检测到之前消失时， 这个过程被称为消逝。抗体消失的患者会在不知不觉中 第二次输入不相容的血液这种不相容的输血会导致危及生命的事件 称为迟发性溶血性输血反应。因此，抗RBC消失直接导致延迟的 溶血性输血反应是慢性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， 输血和有很高的渐逝性抗体的比率。尽管它的临床重要性，分子 导致抗RBC同种抗体消失的因素是完全未知的。因此，没有 有效的治疗干预措施可用于同种免疫患者，而不是抗原回避。我们有 最近有了新的发现，红细胞同种免疫的HOD小鼠模型 概括了在慢性输血患者中观察到的许多关键临床特征。具体来说，我们有 表明HOD RBC输注导致低亲和力、快速消失的抗- RBC同种抗体以高亲和力持久抗体为代价。在此，我们建议使用此鼠标 研究为什么红细胞输注会导致快速消失的抗体而不是长寿命的抗体。 我们的中心假设是，红细胞抗原呈递直接改变了先天性免疫反应， 受体，驱动CD 4 + T细胞分化为辅助细胞，无法维持长寿命 与B细胞的相互作用。我们假设，虽然这些T细胞可以驱动滤泡外抗体反应， 产生低亲和力、短寿命的抗体，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应答 产生浆细胞。通过更好地理解基本的细胞和分子免疫 抗红细胞同种抗体的调节因子随时间而调节，我们希望发现新的分子靶点 这可以作为潜在的未来疗法，用于那些并发症风险高的患者， RBC同种异体免疫