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 尽管兰德斯坦纳在一个多世纪前发现了ABO(H)血型抗原，使得人们能够预测 红细胞(RBC)的配型在输血前，在20世纪30年代的几项研究中证明RBC 输血本身也可以诱导更多的红细胞同种异体抗体，从而导致不相容的输血。 反应。RBC诱导的针对各种不同RBC同种抗原的同种异体抗体可以变得特别 对需要重复输血的人来说是个问题，经常使人很难找到，如果不是不可能的话 相容的红细胞。因此，RBC同种异体抗体的形成可显著增加死亡率和 需要长期输血的患者的发病率。然而，目前还不存在主动抑制的策略 RBC输注治疗后RBC诱导的同种异体抗体形成。这在一定程度上反映了缺乏 了解调节RBC诱导的同种异体抗体形成的关键启动因素。为了 开发有可能抑制RBC诱导的同种抗体形成的策略，我们最近使用了 开发了RBC同种异体免疫的小鼠模型，以定义生产 暴露于两种不同的红细胞同种异体抗原后产生的红细胞同种异体抗体。我们的初步结果 证明去除边缘带内的B细胞或巨噬细胞可预防同种异体抗体 在接触两种不同的红细胞同种异体抗原后形成。然而，这些独特的红细胞同种异体抗原 似乎不同地诱导MZ成分与1型干扰素(干扰素αβ)或Toll样受体结合 小路。此外，我们的初步数据表明，RBC同种异体抗原也具有 在红细胞输注后诱导非依赖于或依赖于CD4+T细胞的抗体形成。AS 以前的研究表明，边缘带巨噬细胞(MZM)和MZ B细胞可以协同工作 诱导非依赖于或依赖于CD4+T细胞的免疫反应，这些结果表明 MZM和MZ B细胞通过CD4+T细胞产生抗RBC同种异体抗体的关键环节 细胞非依赖和CD4+T细胞依赖的过程，取决于所呈现的RBC同种异体抗原的类型。 因此，我们假设MZ成分在启动和协调MZ成分中发挥核心作用 输注红细胞引起的免疫反应。为了验证这一假设，我们提出了以下具体建议 目的：1)明确MZB细胞和MZM在干扰素αβ诱导的T细胞非依赖性红细胞同种异体抗体中的作用 队形。2)明确MZM和MZB细胞在CD4+T细胞依赖的RBC同种抗体中的作用 队形。我们相信，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启动因素 对不同的红细胞同种异体抗原的免疫反应的关键。在此过程中，这些研究将提供有价值的 多种RBC抗原的同种异体免疫反应在治疗中的潜在靶点 需要长期输血治疗的患者。