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

• 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
• 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

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 缺乏足够的兼容红细胞单位。此外，红细胞同种抗体可导致溶血病。 胎儿和新生儿。因此，红细胞同种免疫问题对于许多人来说具有重要意义。 患者。抗体传统上被认为是适应性免疫系统的一部分，它形成了 仅在接触抗原后才产生反应；然而，近年来，一类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 免疫。大多数 nAb 是 IgM (nIgM)，其特异性有限，包括自身抗原 受损组织的决定因素。首先存储输注的所有红细胞单位，从而产生 细胞损伤的特征模式，包括已知 nIgM 靶标的表达。在动物模型中，我们 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 在一些后续的人类研究中观察到。在这种情况下，本申请将检验 nIgMs 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 呈递、T 细胞激活和 B 细胞成熟。除 nIgM 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，输注的红细胞继续循环至 100- 人类 120 天（小鼠 50 天）。因此，适应性 IgG 可以在初级阶段与循环红细胞结合。 免疫反应，有可能影响正在进行的红细胞同种免疫。事实上，我们提供了新颖的数据 抗红细胞 IgG 对正在进行的红细胞同种免疫具有调节作用。在此背景下，建议 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 增加后续免疫力。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。