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.

项目摘要/摘要 镰状细胞病(SCD)患者的红细胞(RBC)异基因免疫率显著较高 而不是其他接受输血捐献者红细胞的人群。根据研究情况，输血情况， 据报道，18-47%的SCD患者对RBC异种免疫。 输血后的抗原，也更有可能产生额外的同种异体抗体 输血。在急性SCD并发症的环境中输血的优势比(1)高8-12倍。 导致同种异体抗体的形成，与在稳定状态下给出的抗体相比。我们假设我们会发现 同种异体免疫的关键驱动因素是一项大规模、公正的人体研究，该研究整合了受体经济学和 当时的环境条件(即是否有急性疾病和高度炎症) 输血。我们将首先通过分析识别与同种异体免疫相关的变体来测试这一点 来自应答者和非应答者的基因组测序(WGS)。我们假设患有SCD的人 非洲遗产将具有与增强免疫原性相关的基因变异。为了测试这一点，我们将 分析我们的Emory SCD队列(n=2000)在10岁以后有或没有出现同种抗体的WGS 或更多的输血，与TOPMed的REDS III队列中的WGS相比，后者有 2800例巴西SCD患者的同种异体免疫表型。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 有或没有发生异基因免疫的SCD患者。我们假设我们能识别出基因的变化 与同种异体免疫相关的表达(及相关途径)。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)，如果 确定合理开发治疗干预措施的途径。最后，我们将评估 同种异体免疫的炎症反应。我们假设发生在SCD患者身上的异基因免疫 急性炎症的环境与环境中发生的同种异体免疫有机械上的不同 在慢性输血或健康个体中。我们会将在目标2中获得的抄本与 从存储的PBMC中获得的scRNAseq数据来自40名患有 同种异体抗体被Rh不匹配的红细胞攻击时。我们预测我们的分析将使我们能够确定 在异体免疫发生前处于危险中的个体，并阐明炎症在 SCD患者和健康人的同种异体免疫。