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; 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.

概括。对于需要慢性输血的患者，生成红细胞的抗体（RBC） 抗原可能是一个主要的临床问题。抗RBC抗体通常使发现兼容血液困难 对于这些患者而言，这尤其不幸，因为这些RBC输血通常是挽救生命的。专业 当这些抗RBC同种抗体在血库中检测前消失时，就会出现并发症 过程称为消亡。抗体消失的患者可以在不知不觉中接受 不兼容的血液的第二次输血。这种不兼容的输血会引起威胁生命的事件 称为延迟溶血输血反应。因此，抗RBC ivansenccenccIC直接导致延迟 溶血输血反应是慢性输血患者损伤和死亡的主要原因。 对于镰状细胞疾病的患者而言，这是一个特别严重的问题，他们通常需要频繁 输血且具有较高的逃生抗体。尽管其临床重要性，但分子 导致抗RBC同种抗体逃生的因素是完全未知的。因此，没有 除了抗原避免抗原以外，还可以提供有效的治疗干预措施。我们有 最近提出了新的发现，即红细胞的HOD小鼠模型（RBC）同种免疫 概括了长期输血患者中看到的许多关键临床特征。具体来说，我们有 表明HOD RBC输血导致低亲和力的优先产生 RBC同种抗体以高亲和力，持续的抗体为代价。在此我们建议使用此鼠标 研究RBC输血导致迅速逃生的抗体而不是长寿命的模型。 我们的中心假设是抗原的RBC表现直接改变了先天免疫反应 接受者，将CD4+ T细胞的分化驱动到无法维持长寿的辅助细胞中 与B细胞的相互作用。我们假设，尽管这些T细胞可以驱动外流体抗体反应 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塞 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 抗RBC同抗体的调节剂会随着时间的流逝而受到调节，我们希望发现新的分子靶标 对于那些因并发症而处于高风险的患者来说，这可以作为未来的治疗方法 加拿大皇家银行同种免疫。