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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.

总结。对于需要长期输血的患者，红细胞抗体的产生