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.

总结。对于需要长期输血的患者，红细胞抗体的产生 抗原可能是一个主要的临床问题。抗RBC抗体经常使寻找相容血液变得困难 对于这些患者来说，这特别不幸，因为这些红细胞输注通常是挽救生命的。一位少校 当这些抗红细胞同种异体抗体在血库中检测到之前消失时，就会出现并发症。 这一过程被称为消逝。抗体消失的患者可能在不知不觉中收到 第二次输不相容的血。这种不相容的输血可能会引发危及生命的事件 称为延迟溶血性输血反应。因此，抗红细胞消逝直接导致延迟 溶血性输血反应，这是慢性输血患者受伤和死亡的主要原因。 对于患有镰状细胞病的患者来说，这是一个特别严重的问题，他们经常需要 输血并有很高的抗体消失率。尽管它具有临床重要性，但分子 导致抗RBC同种异体抗体消失的因素是完全未知的。因此，没有 对异体免疫的患者可采取有效的治疗干预措施，而不是避免抗原。我们有 最近新近发现HOD小鼠模型对红细胞(RBC)的同种免疫 总结了许多在慢性输血患者中看到的关键临床特征。具体来说，我们有 结果表明，HOD红细胞输注可优先产生低亲和力、快速消逝的抗-HBc。 红细胞同种异体抗体以高亲和力、持久性抗体为代价。在这里，我们建议使用这个鼠标 模型来研究为什么输血红细胞会导致快速消逝的抗体，而不是长寿的抗体。 我们的中心假设是，红细胞呈递抗原直接改变先天免疫反应。 受体，推动CD4+T细胞分化为无法长期生存的辅助细胞 与B细胞的相互作用。我们推测，尽管这些T细胞可以驱动卵泡外抗体反应 产生低亲和力、短命抗体，它们驱动生发中心的能力受阻 允许体细胞高度突变、抗体亲和力成熟和抗体长寿的反应 产生浆细胞。通过更好地了解基础细胞和分子免疫是如何 抗RBC同种异体抗体的调节是随着时间的推移而调节的，我们希望发现新的分子靶点 这可以作为未来潜在的治疗方法，用于那些有高并发症风险的患者。 红细胞同种异体免疫。