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: 9981001
• 负责人: Nourine Ahmed Kamili
• 金额: $ 2.95万
• 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/9981001
• 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.

项目摘要 尽管ABO（H）血型抗原和相应的抗ABO（H）抗体的发现超过了一个世纪， 世纪前，抗ABO（H）抗体仍然是输血最重要的免疫屏障之一 和移植。此外，负责抗血型抗体形成的机制及其 监管相对来说还是未知的。先前的研究表明，暴露于表达 与ABO（H）抗原相似的膜碳水化合物结构可能是形成ABO（H）抗原的驱动力。 天然存在的抗ABO（H）血型抗体。为了检验血型表达的作用 微生物暴露在抗血型抗体形成的发展，我们产生了一种新的动物 缺乏小鼠血型B二糖（Bdis）的模型，产生类似于 O型血的人。初步研究表明，Bdis阴性受体被安置在标准的 条件下容易产生高滴度的抗Bdis抗体，而无特定病原体（SPF） 在某些条件下，直到成年期暴露于Bdis阳性微生物时才能产生抗Bdis抗体。 综上所述，这些发现表明，微生物暴露可能需要天然存在的抗Bdis 抗体发展额外的初步数据表明，在年轻时接触微生物 导致更大数量的抗体产生。然而，这些高抗体滴度不能持续在 受体中恒定的水平，这可能反映了Bdis阳性的持续定殖的改变， 细菌这些结果与抗ABO（H）抗体显著差异的临床观察结果一致 个体之间的关系。考虑到不同年龄组的抗体水平和居住条件的差异， Bdis阴性模型，我们假设微生物暴露的时间和持续时间影响 抗血型抗体产生的幅度和持久性。为了验证这一假设，我们建议 具体目标如下：目标1。确定受体年龄对抗Bdis发展的影响 抗ABO（H）溶血性输血反应相关抗体。目标二。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血液中的作用提供新的见解。 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。