Regulation of RBC Alloimmunization by Naturally Occurring and Adaptive Antibodies

天然存在和适应性抗体对红细胞同种免疫的调节

基本信息

批准号：
9381275
负责人：
Krystalyn E Hudson
金额：
$ 41.13万
依托单位：
BLOODWORKS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-23 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381275
关键词：
Adaptive Immune System Affect Alloantigen Alloimmunization American Americas Animal Model Animals Antibodies Antigen Presentation Antigen-Presenting Cells Antigens B-Lymphocytes Binding Biology CD4 Positive T Lymphocytes Cell Maturation Cell surface Cells Characteristics Chronic Data Disease Dissection Epitopes Erythrocyte Transfusion Erythrocytes Exposure to Fetus Frequencies Generations Genetic Recombination Glycoproteins Goals Hour Human IgG1 IgG2 IgG3 IgG4 Immune response Immune system Immunity Immunization Immunoglobulin G Immunoglobulin M Immunoglobulin Variable Region Infection Infusion procedures Innate Immune System Isoantibodies Kinetics Knockout Mice Lead Light Mediating Microbe Modality Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Mutation Natural Immunity Newborn Infant Patients Pattern Physiologic pulse Process Recombinants Regulation Reporting Role Signal Transduction Specificity Stimulus Surface System T-Cell Activation T-Cell Receptor Testing Therapeutic Therapeutic Intervention Time Tissues Transfusion Transgenic Organisms Translations adaptive immune response adaptive immunity antigen binding base cell injury follow-up humanized antibody humanized mouse immunogenic immunogenicity innovation isoimmunity microbial mortality mouse model novel pathogen pathogen exposure pre-clinical prevent receptor response

项目摘要

RBC transfusion is the single most common therapeutic modality given to patients in America, with approximately 1 out of every 70 Americans being transfused each year. Some chronically transfused patients become alloimmunized against many of the over 340 RBC alloantigens, leading to morbidity and mortality due to lack of sufficient compatible RBC units. In addition, RBC alloantibodies can lead to hemolytic disease of the fetus and newborn. Thus, issues of RBC alloimmunization are of high significance to a large number of patients. Antibodies have traditionally been considered part of the adaptive immune system, which forms a response only after exposure to antigen; however, in recent years a new class of pre-existing antibodies (naturally occurring antibodies (nAbs)) have been described that bridge the gap between innate and adaptive immunity. Most nAbs are IgM (nIgMs) that have a limited range of specificities, including autoantigenic determinants on damaged tissues. All units of RBCs that are transfused are stored first, resulting in characteristic patterns of cell damage, including expression of known nIgMs targets. In animal models, we have reported that storage of RBCs increases RBC alloimmunization upon transfusion, a finding that has been observed in some follow up human studies. In this context, this applicaiton will test the hypothesis that nIgMs, pre-existing in naïve animals, are involved in increased immunogenicity of stored RBCs through binding conserved motifs that are increased on the RBC surface of stored RBCs, leading to altered antigen presentation, T cell activation and B cell maturation. In addition to nIgMs, normal adaptive IgG to RBC alloantigens can be detected as early as 7-12 days; however, transfused RBCs continue to circulate up to 100- 120 days in humans (50 days in mice). Thus adaptive IgGs can bind to circulating RBCs during a primary immune response, with the potential to affect ongoing RBC alloimmunization. Indeed, we present novel data that anti-RBC IgG, has regulatory effects upon ongoing RBC alloimmunization. In this context, the proposed studies will also test the hypothesis that adaptive anti-RBC IgGs affect ongoing alloimmunization by shuttling antigen to more immunogenic antigen-presenting cells, activation of the antigen-presenting cells, and increased subsequent immunity. These two hypotheses are investigated in the context of 3 specific aims: Specific aim 1: Determine the role of nIgM in initiating adaptive alloimmunity to RBC transfusion Specific aim 2: Mechanisms by which anti-RBC antibodies alter adaptive humoral alloimmunization. Specific aim 3: Test the effects of anti-RBC alloantibodies upon ongoing RBC alloimmunization in a humanized mouse model. These aims use innovative approaches to test mechanistic biology, at both the cellular and molecular level, and also generate an initial bridge to translation into human studies in aim 3.

红细胞输血是美国患者最常见的单一治疗方式，每年大约每 70 名美国人中就有 1 人接受输血一些长期输血的患者。对 340 多种红细胞同种抗原中的许多种进行同种免疫，导致发病率和死亡率缺乏足够的相容红细胞单位此外，红细胞同种抗体可导致溶血病。因此，红细胞同种免疫问题对于许多人来说具有重要意义。抗体传统上被认为是适应性免疫系统的一部分，形成了免疫系统。仅在接触抗原后才会产生反应；然而，近年来出现了一种新的预先存在的抗体（天然存在的抗体（nAb））已被描述为弥补先天性和适应性之间的差距大多数 nAb 是 IgM (nIgM)，其特异性有限，包括自身抗原。首先储存所有输注的红细胞单位，从而导致细胞损伤的特征模式，包括在动物模型中已知的 nIgM 靶标的表达。据报道，红细胞的储存会增加输血后红细胞的同种免疫，这一发现已被证实在一些后续人类研究中观察到，在这种情况下，本应用将检验 nIgM 的假设。预先存在于幼稚动物中，通过结合参与增加储存的红细胞的免疫原性保存的红细胞的红细胞表面上增加的保守基序，导致抗原改变除了 nIgM 之外，还有针对红细胞的正常适应性 IgG。最早可在 7-12 天检测到同种异体抗原；然而，输注的红细胞可持续检修长达 100-10 天。人类为 120 天（小鼠为 50 天），因此适应性 IgG 可以在原发性期间与循环红细胞结合。免疫反应，有可能影响正在进行的红细胞同种免疫确实，我们提供了新的数据。抗红细胞 IgG 对正在进行的红细胞同种免疫具有调节作用。研究还将检验适应性抗红细胞 IgG 通过穿梭影响正在进行的同种免疫的假设将抗原转化为更具免疫原性的抗原呈递细胞，激活抗原呈递细胞，以及增加随后的免疫力。这两个假设是在 3 个具体目标的背景下进行研究的：具体目标 1：确定 nIgM 在启动红细胞输注适应性同种免疫中的作用具体目标 2：抗红细胞抗体改变适应性体液同种免疫的机制。具体目标 3：在人源化小鼠模型中测试抗红细胞同种抗体对正在进行的红细胞同种免疫的影响。这些目标使用创新方法在细胞和分子水平上测试机械生物学，并为目标 3 中的人类研究搭建一个初步的桥梁。