Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion. Project 4

红细胞输注同种免疫的基本和转化机制。

• 批准号: 10711671
• 负责人: Vivien Andrea Sheehan
• 金额: $ 48.48万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711671
• 关键词: Acute; African; Alloantigen; Alloimmunization; Antigens; B-Cell Antigen Receptor; Blood Transfusion; Brazil; Cells; Chromosomes; Chronic; Classification; Complication; Data; Environment; Erythrocyte Transfusion; Erythrocytes; Event; Exposure to; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Haplotypes; Immunize; Immunoglobulin G; Individual; Inflammation; Inflammatory; Isoantibodies; Leukocytes; Medical; Methods; Molecular; Monitor; Odds Ratio; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposing Factor; Publishing; RNA; Reporting; Resources; Risk; Role; Sampling; Serology; Services; Sickle Cell Anemia; Testing; Therapeutic Intervention; Time; Trans-Omics for Precision Medicine; Transfusion; Variant; admixture mapping; cohort; genetic risk factor; genetic variant; genome analysis; genome sequencing; human study; immunogenicity; insight; novel; prospective; responders and non-responders; response; therapeutic development; transcriptome; whole genome

Project Summary/Abstract Individuals with sickle cell disease (SCD) have a significantly higher red blood cell (RBC) alloimmunization rate than other populations receiving transfused donor RBCs. Depending on the study, circumstances of transfusion, and environment, it has been reported that 18-47% of individuals with SCD become immunized to RBC allo- antigens following a transfusion and are also more likely to then make additional alloantibodies with subsequent transfusions. Transfusions in the setting of an acute SCD complication have an 8-12-fold higher odds ratio(1) of resulting in alloantibody formation compared to those given at steady-state. We hypothesize that we will identify key drivers of alloimmunization with a large-scale, unbiased human study that integrates recipient omics and environmental conditions (i.e., presence or absence of acute illness and high levels of inflammation) at the time of transfusion. We will test this through first identifying variants associated with alloimmunization through analysis of genome sequencing (WGS) from responders and non-responders. We hypothesize that SCD individuals with African heritage will have genetic variants associated with increased immunogenicity. To test this, we will analyze the WGS of our Emory SCD cohort (n=2000) who have or have not developed alloantibodies after 10 or more blood transfusions and compare to WGS from the REDSIII cohort in TOPMed, which has alloimmunization phenotypes on 2800 subjects with SCD from Brazil. Then, we will assess transcriptome changes of leukocyte subsets at baseline, at time of transfusion, and at one-month post-transfusion in individuals with SCD who did or did not develop alloimmunization. We hypothesize that we will identify alterations in gene expression (and affiliated pathways) that associate with alloimmunization. This will have the immediate benefit of allowing us to develop a transcriptional risk score (TRS) for alloimmunization, and the longer-term benefit if identifying pathways for rational development of therapeutic interventions. Finally, we will assess the impact of inflammation on alloimmunization. We hypothesize that alloimmunization in individuals with SCD that occur in the setting of acute inflammation differs mechanistically from that of alloimmunization that occurs in the setting of chronic transfusion or in healthy individuals. We will compare the transcriptomes obtained in aim 2 to scRNAseq data obtained from stored PBMCs from a cohort of 40 non-SCD individuals who developed alloantibodies when challenged by Rh mismatched RBCs. We predict our analysis will allow us to identify individuals at risk for alloimmunization before it occurs, and elucidate the role of inflammation in alloimmunization, both in patients with SCD and in healthy individuals.

项目概要/摘要 镰状细胞病 (SCD) 患者的红细胞 (RBC) 同种免疫率明显较高 高于接受捐献者红细胞输注的其他人群。根据研究、输血情况， 和环境，据报道，18-47% 的 SCD 患者对红细胞同种异体免疫 输血后产生抗原，并且也更有可能在随后的过程中产生额外的同种抗体 输血。发生急性 SCD 并发症时输血的比值比高出 8-12 倍(1) 与稳态时相比，导致同种抗体形成。我们假设我们将识别 通过一项大规模、公正的人类研究，整合了受者组学和 当时的环境条件（即是否存在急性疾病和高水平炎症） 输血。我们将首先通过分析识别与同种免疫相关的变异来测试这一点 对有反应者和无反应者进行基因组测序（WGS）。我们假设 SCD 个体 非洲血统将具有与免疫原性增强相关的遗传变异。为了测试这一点，我们将 分析我们的埃默里 SCD 队列 (n=2000) 的全基因组测序 (WGS)，这些队列在 10 年后已产生或尚未产生同种抗体 或更多输血，并与 TOPMed 中 REDSIII 队列的 WGS 进行比较，该队列已 来自巴西的 2800 名 SCD 受试者的同种免疫表型。然后，我们将评估转录组 个体在基线、输血时和输血后 1 个月时白细胞亚群的变化 患有 SCD 的人已进行或未进行同种免疫。我们假设我们将识别基因的改变 与同种免疫相关的表达（和附属途径）。这将带来立竿见影的好处 允许我们开发同种免疫的转录风险评分（TRS），以及如果 确定合理发展治疗干预措施的途径。最后，我们将评估影响 同种免疫引起的炎症。我们假设患有 SCD 的个体发生同种免疫 急性炎症的情况在机制上不同于该情况中发生的同种免疫 慢性输血或健康个体。我们将比较目标 2 中获得的转录组 scRNAseq 数据从 40 名非 SCD 个体的储存 PBMC 中获得， 当受到 Rh 不匹配的红细胞攻击时产生同种抗体。我们预测我们的分析将使我们能够识别 在同种免疫发生之前对处于同种免疫风险的个体进行研究，并阐明炎症在其中的作用 同种免疫，适用于 SCD 患者和健康个体。