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 患有镰状细胞病（SCD）的个体具有明显更高的红细胞（RBC）同种异体率 比其他接收输血供体RBC的人群。根据研究，输血的情况， 和环境，据报道，有18％至47％的SCD患者被免疫到RBC Allo- 输血后的抗原，并且更有可能进行额外的同抗体，随后 输血。急性SCD并发症的环境中的输血的几率比（1）高8-12倍 与在稳态下给出的相比，导致同种抗体形成。我们假设我们将确定 通过大规模，公正的人类研究的主要驱动力驱动器，该研究整合受者omics和 当时的环境状况（即存在或不存在急性疾病和高水平的炎症） 输血。我们将通过首先识别与同种免疫化相关的变体进行测试 来自反应者和非反应者的基因组测序（WGS）。我们假设SCD个人与 非洲遗产将具有与免疫原性增加有关的遗传变异。为了测试这一点，我们将 分析我们的Emory SCD队列（n = 2000）的WG，他们在10后具有或未开发同种抗体 或更多的输血，并与Topmed中的RedSIII队列进行比较， 来自巴西的SCD对2800名受试者的同种免疫表型。然后，我们将评估转录组 在基线，输血时和个体后1个月后，白细胞子集的变化 与SCD有关或未开发同种免疫化的SCD。我们假设我们将确定基因的变化 与同种免疫相关的表达（和关联途径）。这将带来直接的好处 允许我们为同种免疫的转录风险评分（TRS），以及长期的收益 确定治疗干预措施合理发展的途径。最后，我们将评估 同种免疫的炎症。我们假设在发生在SCD的个体中的同种异体免疫 急性炎症的设置机理上不同于在环境中发生的同种免疫。 慢性输血或健康个体。我们将比较AIM 2中获得的转录组与 从40个非SCD个体的队列中获得的SCRNASEQ数据 当受RH不匹配的RBC挑战时，同种抗体。我们预测我们的分析将使我们能够确定 在发生同种异体免疫风险之前，炎症在发生之前的风险 在患有SCD的患者和健康个体的患者中，同种免疫化。