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: 10223410
• 负责人: Nourine Ahmed Kamili
• 金额: $ 1.16万
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223410
• 关键词: ABO blood group system; Adult; Age; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Applications Grants; B-Lymphocyte Subsets; Bacteria; Blood Group Antigens; 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; natural antibodies; 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.

项目概要 尽管 ABO(H) 血型抗原和相应的抗 ABO(H) 抗体在 一个世纪前，抗 ABO(H) 抗体仍然是输血最重要的免疫障碍之一 和移植。此外，抗血型抗体形成的机制及其 监管仍然相对未知。先前的研究表明，接触表达微生物 类似于 ABO(H) 抗原的膜碳水化合物结构可能是形成 天然存在的抗 ABO(H) 血型抗体。为了检查血型表达的作用 在抗血型抗体形成的过程中接触微生物，我们培育出了一种新型动物 缺乏小鼠 B 型血二糖 (Bdis) 的模型，生成类似于 人类O型血个体。初步研究表明，Bdis 阴性接受者被安置在标准环境中 条件下很容易产生高滴度的抗 Bdis 抗体，而那些置于无特定病原体 (SPF) 中的抗体 除非成年后接触 Bdis 阳性微生物，否则无法产生抗 Bdis 抗体。 总而言之，这些发现表明，天然存在的抗 Bdis 可能需要接触微生物 抗体开发。其他初步数据表明，年轻时接触微生物 导致更大量的抗体产生。然而，这些高抗体滴度无法持续 接受者中水平恒定，这可能反映了 Bdis 阳性持续定植的变化 细菌。这些结果与抗 ABO(H) 抗体显着差异的临床观察结果相似 个体之间。鉴于不同年龄组和居住条件的抗体水平存在差异 Bdis 负模型，我们假设微生物暴露的时间和持续时间会影响 抗血型抗体产生的强度和持久性。为了检验这个假设，我们提出 具体目标如下： 目标 1. 明确接受者年龄对抗 Bdis 发展的影响 与抗 A​​BO(H) 溶血性输血反应相关的抗体。目标 2. 定义持续的要求 与溶血性输血相关的抗 Bdis 抗体持续产生的微生物暴露 反应。这些研究将为表达血型的微生物在 抗 ABO(H) 抗体的产生和持续存在，这是最常见的免疫屏障 移植和输血治疗。