Characterization of Naturally Occurring Anti-Blood Group Antibody Formation

天然存在的抗血型抗体形成的表征

• 批准号: 9397073
• 负责人: Nourine Ahmed Kamili
• 金额: $ 4.4万
• 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: 2017-07-31 至 2022-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397073
• 关键词: ABO blood group system; Adult; Age; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; Applications Grants; B-Lymphocyte Subsets; Bacteria; Clinical; Data; Dependence; Development; Disaccharides; Environment; Environmental Risk Factor; Erythrocytes; Exposure to; Genetic; Goals; House mice; Housing; Human; Immunologics; Individual; Life; Mediating; Membrane; Microbe; Modeling; Mus; Nature; Play; Production; Reaction; Regulation; Role; System; Testing; Transfusion; Transplantation; Variant; Weaning; age group; bacterial H antigen; blood group; carbohydrate structure; cell type; driving force; germ free condition; insight; microbial; mouse model; novel

PROJECT SUMMARY Despite the discovery of ABO(H) blood group antigens and corresponding anti-ABO(H) antibodies over a century ago, anti-ABO(H) antibodies remain one of the most significant immunological barriers to transfusion and transplantation. Moreover, the mechanisms responsible for anti-blood group antibody formation and its regulation remain relatively unknown. Previous studies suggest that exposure to microbes expressing membrane carbohydrate structures resembling ABO(H) antigens may be a driving force in the formation of naturally occurring anti-ABO(H) blood group antibodies. In order to examine the role of blood group expressing microbe exposure in the development of anti-blood group antibody formation, we generated a novel animal model that lacks the mouse blood group B disaccharide (Bdis), generating a recipient that is analogous to human blood group O individuals. Preliminary studies indicate that Bdis negative recipients housed in standard conditions readily produce anti-Bdis antibodies at high titers, while those housed in specific pathogen free (SPF) conditions are unable to produce anti-Bdis antibodies until exposed to Bdis positive microbes in adulthood. Taken together, these findings suggest that microbial exposure may be required for naturally occurring anti-Bdis antibody development. Additional preliminary data demonstrate that exposure to microbes at a younger age results in a greater magnitude of antibody production. However, these high antibody titers fail to persist at constant levels among recipients, which may mirror alterations in sustained colonization of Bdis positive bacteria. These results parallel clinical observations regarding significant differences in anti-ABO(H) antibodies between individuals. Given this variability in antibody levels across age groups and housing conditions of the Bdis negative model, we hypothesize that the timing and duration of microbial exposure impacts the magnitude and persistence of anti-blood group antibody production. To test this hypothesis, we propose the following specific aims: Aim 1. Define the impact of recipient age on the development of anti-Bdis antibodies relevant in anti-ABO(H) hemolytic transfusion reactions. Aim 2. Define the requirement of continued microbial exposure for the persistent production of anti-Bdis antibody relevant to hemolytic transfusion reactions. These studies will provide novel insight into the role blood group expressing microbes play in the production and persistence of anti-ABO(H) antibodies, the most common immunological barrier to transplantation and transfusion therapy.

项目摘要 尽管发现了ABO（H）血型抗原和相应的抗ABO（H）抗体 世纪前，抗Abo（H）抗体仍然是输血的最重要的免疫障碍之一 和移植。此外，负责抗卵组抗体形成及其的机制 法规仍然相对未知。先前的研究表明，暴露于表达的微生物 类似于ABO（H）抗原的膜碳水化合物结构可能是形成的驱动力 天然发生的抗ABO（H）血型抗体。为了检查表达血型的作用 在抗血细胞组抗体形成的开发中，微生物暴露，我们产生了一种新型动物 缺乏小鼠血液B二糖（BDI）的模型，产生了类似于 人类血型o个个人。初步研究表明，标准中容纳的BDI负面受体 条件很容易在高滴度下产生抗BDIS抗体，而在特定病原体（SPF）中容易产生抗BDIS抗体 条件无法产生抗BDIS抗体，直到成年后暴露于BDIS阳性微生物。 综上所述，这些发现表明自然发生的抗BDI可能需要微生物暴露 抗体开发。其他初步数据表明，年轻时接触微生物 导致更大的抗体产生。但是，这些高抗体滴度无法持续 接收者之间的恒定水平，这可能反映了bdis阳性持续定殖的改变 细菌。这些结果平行于抗ABO（H）抗体显着差异的临床观察结果 在个人之间。鉴于年龄组之间的抗体水平和住房条件的这种差异 BDIS负模型，我们假设微生物暴露的时间和持续时间影响 抗血液组抗体产生的大小和持久性。为了检验这一假设，我们提出了 以下具体目的：目标1。定义受体年龄对抗BDI的发展的影响 与抗ABO（H）溶血输血反应相关的抗体。目标2。定义持续的要求 微生物暴露于与溶血输血相关的抗BDIS抗体的持续产生 反应。这些研究将为表达微生物在 抗ABO（H）抗体的生产和持久性，这是最常见的免疫障碍 移植和输血疗法。