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: 10160944
• 负责人: Krystalyn E Hudson
• 金额: $ 36.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160944
• 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; Consumption; 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 response; 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.

RBC输血是美国患者的最常见热方式， 每年有70名美国人中，大约有1个被输出。一些长期输血的患者 与许多超过340个RBC同种抗菌素中的许多同种免疫，从而导致发病率和死亡率 缺乏足够的兼容RBC单元。此外，RBC同种抗体可能导致 胎儿和新生儿。这就是RBC同种免疫的问题对大量 患者。传统上，抗体被认为是自适应免疫系统的一部分，该系统形成了 仅在暴露于抗原后的反应；但是，近年来，一类新的预先存在的抗体 （自然发生的抗体（NABS））已被描述为桥接先天和适应性之间的差距 免疫。大多数NAB是IgM（NIGM），其特异性范围有限，包括自身抗原 损坏的组织的决定因素。首先存储所有被输血的RBC的单位，从而导致 细胞损伤的特征模式，包括已知的NIGMS目标的表达。在动物模型中，我们 报道说，RBC的存储在输血后增加了RBC同种免疫化，这一发现已经 在一些后续研究中观察到。在这种情况下，该涉及的人将测试裸体的假设，即 通过结合，幼稚动物的先前存在的RBC的免疫原性涉及增加的免疫原性 在储存的RBC的RBC表面上增加的保守基序，导致抗原改变 表现，T细胞活化和B细胞成熟。除了nigms，正常自适应IgG对RBC 早在7-12天之前就可以检测到同种剂；但是，输血的RBC继续循环多达100-- 人类为期120天（小鼠50天）。自适应IgG可以在初级期间与循环的RBC结合 免疫反应，有可能影响正在进行的RBC同种免疫化。确实，我们提出了新的数据 该抗RBC IgG对正在进行的RBC同种免疫具有调节作用。在这种情况下，提议 研究还将检验以下假设，即自适应抗RBC IgG会通过穿梭来影响正在进行的同种免疫 抗原与更多免疫原性抗原细胞，抗原呈递细胞的激活，以及 随后的免疫力增加。这两个假设在3个具体目的的背景下进行了研究： 特定目标1：确定NIGM在启动对RBC输血特定的自适应同种异体中的作用 AIM 2：抗RBC抗体改变适应性体液同种异体免疫的机制。具体目标3： 在人源化小鼠模型中测试抗RBC同抗体对持续的RBC同anmumumization的影响。 这些目的使用创新的方法在细胞和分子水平上测试机械生物学， 并在AIM 3中产生了将翻译成人类研究的初始桥梁。

项目成果

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization.

• DOI: 10.3389/fimmu.2022.972723
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Antibodies to Low-Copy Number RBC Alloantigen Convert a Tolerogenic Stimulus to an Immunogenic Stimulus in Mice.

• DOI: 10.3389/fimmu.2021.629608
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Jash A;Usaneerungrueng C;Howie HL;Qiu A;Luckey CJ;Zimring JC;Hudson KE
• 通讯作者: Hudson KE