Characterization of Naturally Occurring Anti-Blood Group Antibody Formation

项目总结 尽管在过去的一年中发现了ABO(H)血型抗原和相应的抗ABO(H)抗体 一个世纪前，抗ABO(H)抗体仍然是输血最重要的免疫学障碍之一 和移植。此外，抗血型抗体形成的机制及其与抗血型抗体的关系 监管仍然相对不为人所知。先前的研究表明，暴露在微生物中表达 膜上类似ABO(H)抗原的碳水化合物结构可能是形成 自然产生的抗ABO(H)血型抗体。为了考察血型表达的作用 在微生物暴露的发展过程中形成抗血型抗体，我们产生了一种新的动物 缺乏小鼠血液B型二糖(BDI)的模型，产生类似于 人类O型血型个体。初步研究显示BDIS阴性受助人入住标准居所 条件很容易产生高滴度的抗Bdis抗体，而那些放置在无特定病原体(SPF)的条件下 在成年后接触BDIS阳性微生物之前，条件是不能产生抗BDIS抗体。 综上所述，这些发现表明，可能需要微生物接触才能自然产生抗BDIS 抗体的发展。更多的初步数据表明，在更年轻的时候接触微生物 结果会产生更多的抗体。然而，这些高抗体效价未能持续在 受体中的恒定水平，这可能反映了BDIS阳性持续定植的变化 细菌。这些结果与关于抗ABO(H)抗体显著差异的临床观察是平行的 在个人之间。鉴于抗体水平在不同年龄组和不同居住条件之间的差异 BDS阴性模型中，我们假设微生物暴露的时间和持续时间会影响 产生抗血型抗体的数量和持久性。为了检验这一假设，我们建议 具体目标如下：目标1.界定受助人年龄对发展反BDIS的影响 与抗ABO(H)溶血性输血反应相关的抗体。目标2.定义继续的要求 持续产生与溶血相关的抗Bdis抗体的微生物暴露 反应。这些研究将为血型表达微生物在疾病中所起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。

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.