Examination of Initiating Factors that Regulate Red Blood Cell Alloimmunization

调节红细胞同种免疫的起始因素的检查

• 批准号: 9922988
• 负责人: Sean R Stowell
• 金额: $ 25.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2020-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922988
• 关键词: ABO blood group system; Alloantigen; Alloimmunization; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Cell Activation; B-Lymphocytes; Blood; Blood Group Antigens; CD4 Positive T Lymphocytes; Chronic; Clinical; Data; Dendritic Cells; Development; Erythrocyte Transfusion; Erythrocytes; Event; Excision; Exposure to; Failure; Generations; Hemoglobinopathies; Hen Egg Lysozyme; Immune; Immune response; Immunologics; Individual; Interferons; Isoantibodies; Lead; Link; Macrophage Activation; Marrow; Modeling; Morbidity - disease rate; Nature; Organ Transplantation; Ovalbumin; Pathway interactions; Patients; Play; Population; Process; Production; Prophylactic treatment; Reaction; Receptor Signaling; Role; Solid; Structure; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Toll-Like Receptor Pathway; Toll-like receptors; Transfusion; Work; cytokine; insight; macrophage; mortality; mouse model; novel; prevent; prophylactic; response; stem; targeted treatment; trafficking

Project Summary Although Landsteiner's discovery of ABO(H) blood group antigens over a century ago allowed predictions of red blood cell (RBC) compatibility prior to transfusion, in the 1930s several studies demonstrated that RBC transfusion itself can also induce additional RBC alloantibodies capable of causing incompatible transfusion reactions. RBC-induced alloantibodies against a variety of distinct RBC alloantigens can become particularly problematic in individuals who require repeat transfusions, often making it difficult, if not impossible, to find compatible RBCs. As a result, RBC alloantibody formation can significantly increase the mortality and morbidity of patients who require chronic transfusions. However, no current strategies exist to actively inhibit RBC-induced alloantibody formation following RBC transfusion therapy. This in part reflects a lack of understanding regarding key initiating factors that regulate RBC-induced alloantibody formation. In order to develop strategies with the potential to inhibit RBC-induced alloantibody formation, we used recently developed mouse models of RBC alloimmunization to define key initiating events required for the production of RBC alloantibodies following exposure to two disparate RBC alloantigens. Our preliminary results demonstrate that removal of marginal zone (MZ) B cells or macrophages within the MZ prevents alloantibody formation following exposure to two distinct RBC alloantigens. However, these unique RBC alloantigens appear to differentially induce MZ constituents to engage type 1 interferon (INFαβ) or toll-like receptor pathways. Furthermore, our preliminary data demonstrate that RBC alloantigens also possess the capacity to induce CD4+ T cell-independent or CD4+ T cell-dependent antibody formation following RBC transfusion. As previous studies suggest that marginal zone macrophages (MZM) and MZ B cells can work in a coordinated fashion to induce CD4+ T cell-independent or CD4+ T cell-dependent immune responses, these results suggest a critical link between MZM and MZ B cells in the generation of anti-RBC alloantibodies through both CD4+ T cell-independent and CD4+ T cell-dependent processes, depending on the type of RBC alloantigen presented. As a result, we hypothesize that MZ constituents play a central role in the initiation and orchestration of immune responses induced by RBC transfusion. To test this hypothesis, we propose the following specific aims: 1) Define the role of MZ B cells and MZM in IFNαβ-induced T cell-independent RBC alloantibody formation. 2) Define the role of MZM and MZ B cells in CD4+ T cell-dependent RBC alloantibody formation. We believe each of these aims provides a unique opportunity to identify common initiating factors key to the immune response to distinct RBC alloantigens. In doing so, these studies will provide valuable insight into potential targets for therapeutic mitigation of alloimmune responses to multiple RBC antigens in patients who require chronic transfusion therapy.

项目摘要 尽管Landsteiner在一个世纪前发现了ABO（H）血型抗原抗原允许预测 在输血之前，红细胞（RBC）兼容性，在1930年代，几项研究表明RBC 输血本身还可以诱导其他RBC同抗体，能够引起不相容的输血 反应。 RBC诱导的同种抗体针对各种不同的RBC同构成剂可能会变得特别 在需要重复输血的个人中有问题，通常会使甚至不可能找到困难（即使不是不可能） 兼容的RBC。结果，RBC同种抗体形成可以显着增加死亡率和 需要慢性输血的患者的发病率。但是，目前尚无积极抑制的策略 RBC诱导的RBC输血疗法后的同种抗体形成。这部分反映了缺乏 了解关键的启动因素，这些因素调节RBC诱导的同种抗体形成。为了 制定具有抑制RBC诱导的同种抗体形成的潜力的策略，我们最近使用了 开发了RBC同截膜化的鼠标模型，以定义生产所需的关键启动事件 暴露于两个不同的RBC同种抗原后，RBC同种抗体。我们的初步结果 证明去除边缘区（MZ）B细胞或MZ内的巨噬细胞可防止同种抗体 暴露于两种不同的RBC同种抗原后的形成。但是，这些独特的RBC同种抗原 出现差异诱导MZ构成以参与1型干扰素（INFαβ）或Toll样接收器 途径。此外，我们的初步数据表明，RBC同种剂也具有 RBC输血后诱导CD4+ T细胞独立或CD4+ T细胞依赖性抗体形成。作为 先前的研究表明，边缘区巨噬细胞（MZM）和MZ B细胞可以在协调中起作用 影响CD4+ T细胞独立或CD4+ T细胞依赖性免疫调查的时尚，这些结果表明 MZM和MZ B细胞之间在抗RBC同种抗体中通过CD4+ T的产生的关键联系 取决于呈现的RBC类型，独立于细胞独立的和CD4+ T细胞依赖性过程。 结果，我们假设MZ在主动性和编排中起着核心作用 RBC输血引起的免疫反应。为了检验这一假设，我们提出以下特定 目的：1）定义MZ B细胞和MZM在IFNαβ诱导的T细胞非依赖性RBC同种抗体中的作用 形成。 2）定义MZM和MZ B细胞在CD4+ T细胞依赖性RBC同种异体中的作用 形成。我们认为，这些目标中的每一个都提供了一个独特的机会来确定共同的初始因素 对不同RBC同种抗原的免疫反应的关键。这样，这些研究将提供有价值的 深入了解对多种RBC抗原的同种异体免疫反应治疗靶标的潜在靶标 需要慢性输血疗法的患者。