Marginal Zone B Cell Regulation of Red Blood Cell Alloimmunization

红细胞同种免疫的边缘区 B 细胞调节

• 批准号: 10192793
• 负责人: Sean R Stowell
• 金额: $ 40.53万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192793
• 关键词: Agonist; Alloantigen; Allogenic; Alloimmunization; Antibody Repertoire; Antibody Specificity; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Blood; Cell physiology; Chronic; Clinical; Clinical Research; Critical Pathways; Data; Development; Erythrocyte Transfusion; Erythrocytes; Event; Failure; Frequencies; Future; Goals; Helper-Inducer T-Lymphocyte; Hemin; Hemoglobinopathies; Immune; Immune Targeting; Immune response; Immunobiology; Individual; Inflammatory; Isoantibodies; Lead; Ligands; Marrow; Mediating; Methods; Morbidity - disease rate; Pathway interactions; Patients; Pre-Clinical Model; Process; Production; Prophylactic treatment; Protocols documentation; Reaction; Regulation; Risk; Role; Sickle Cell Anemia; Specificity; Structure of germinal center of lymph node; Testing; Therapeutic; Therapeutic Intervention; Toll-like receptors; Transfusion; Transplantation; Welding; Work; acute chest syndrome; design; insight; mortality; novel strategies; pre-clinical; preclinical study; prevent; prophylactic; response; stem; trafficking

Project Summary RBC transfusion can induce alloantibodies that can make it difficult to find compatible blood for future transfusions, increase the likelihood of incompatible transfusion reactions, and directly increase morbidity and mortality in patients with sickle cell disease (SCD). Empirical data have shown that although antigen-matching protocols reduce RBC alloimmunization, no currently available strategies completely prevent RBC-induced alloantibody formation following therapeutic transfusion. This in part reflects a lack of understanding regarding key factors responsible for initiating RBC alloimmunization. Our central hypothesis is that marginal zone (MZ) B cells represent a central node in the initiation and orchestration of immune responses to RBC alloantigens, and thus may be a viable immunological target for the development of novel strategies to not only predict, but also prevent RBC alloantibody production. Our hypothesis is formulated on the basis of our recent discovery that MZ B cells are required for the development of RBC alloantibody formation in a pre-clinical model. As MZ B cells can traffic antigen to B cell follicles, the requirement of MZ B cells in RBC alloimmunization may reflect the trapping and subsequent delivery of allogeneic RBCs to B cell follicles, where antigenic substrate is then used by CD4 T follicular helper cells (TFH) to drive effective germinal center reactions responsible for significant alloantibody formation. As antigen trapping requires B cell receptor engagement and MZ B cells possess a restricted and distinct repertoire of antibody specificities in any given individual, these data also suggest that differences in the precursor frequency of RBC alloantigen specific MZ B cells may predict the likelihood that an individual will develop alloantibodies following RBC alloantigen exposure. Furthermore, as toll-like receptor (TLR) agonists can directly increase MZ B cell activity, conditions that directly engage TLRs, such as excess hemin released during acute chest syndrome (ACS) in patients with SCD, may increase the likelihood of RBC alloimmunization by positively impacting MZ B cell function, and therefore may explain in part the increased propensity of patients with SCD to develop RBC alloantibodies. These preliminary data identify MZ B cells as key players in regulating RBC alloantibody formation, and in so doing provide a unique opportunity to define the role of MZ B cells in predicting and preventing RBC alloimmunization. To accomplish this, Project 2 will use a complementary approach of clinical and pre-clinical studies to weld observational data with mechanistic studies in order to define the role of MZ B cells in the regulation of RBC alloimmunization by testing the following specific aims: Aim 1: Define the role of MZ B cells in RBC alloimmunization. Aim 2: Define the impact of ACS on MZ B cell and TFH activation. We believe that successful completion of these aims not only possess the capacity to provide new mechanistic insight into key aspects of RBC alloimmunization, but may also establish an important framework to develop rational approaches designed to prophylactically predict and ultimately prevent RBC alloantibody formation in chronically transfused individuals.

项目摘要 RBC输血可以诱导同种抗体，这可能会使未来找到兼容的血液很难 输血，增加输血反应不相容的可能性，并直接增加发病率和 镰状细胞疾病（SCD）的死亡率。经验数据表明，尽管抗原匹配 协议降低了RBC同义免疫，目前没有可用的策略完全阻止了RBC引起的 治疗输血后的同种抗体形成。这部分反映了对 负责启动RBC同种异体免疫的关键因素。我们的中心假设是边缘区（MZ） B细胞代表了对RBC同种抗原免疫反应的启动和编排的中心节点， 因此，可能是发展新型策略不仅可以预测的新型策略的可行免疫学目标 还可以防止RBC同种抗体产生。我们的假设是根据我们最近的发现提出的 在临床前模型中，RBC同种抗体形成需要MZ B细胞。作为MZ B细胞可以抗原与B细胞卵泡交通，RBC同种异体免疫中MZ B细胞的需求可能反映 随后将同种异体RBC捕获和后续递送到B细胞卵泡中，然后抗原底物是 由CD4 T卵泡辅助细胞（TFH）使用，以驱动有效的生发中心反应 显着的同种抗体形成。由于抗原捕获需要B细胞受体的接合和MZ B细胞 在任何给定的个体中都拥有抗体特异性的受限且独特的曲目，这些数据也 表明RBC同种特异性MZ B细胞的前体频率的差异可能预测 RBC同种抗原暴露后，一个人会形成同种抗体的可能性。此外，AS Toll样受体（TLR）激动剂可以直接增加MZ B细胞活性，即直接吸引TLR的条件， 例如SCD患者急性胸部综合征（AC）期间释放的过量hemin，可能会增加 RBC同种免疫的可能性通过积极影响MZ B细胞功能，因此可以部分解释 SCD患者倾向增加了RBC同种抗体的倾向。这些初步数据识别 MZ B细胞是调节RBC同抗体形成的关键参与者，因此，这样做提供了独特的 定义MZ B细胞在预测和预防RBC同种异体免疫化中的作用的机会。完成 该项目2将使用临床和临床前研究的互补方法来焊接观察数据 通过机械研究来定义MZ B细胞在RBC调节RBC同种异体中的作用 测试以下特定目的：目标1：定义MZ B细胞在RBC同种异体免疫中的作用。目标2： 定义ACS对MZ B细胞和TFH激活的影响。我们相信成功完成这些 目的不仅具有对RBC关键方面的新机械洞察力的能力 同种免疫，但也可能建立一个重要的框架来开发旨在的理性方法 预防性预测并最终预防rbc的同种抗体形成。