Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion Scientific Core A
红细胞输血同种免疫的基本和转化机制 科学核心 A
基本信息
- 批准号:10711667
- 负责人:
- 金额:$ 66.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAdultAfricanAliquotAlloantigenAlloimmunizationBiologyBloodBlood TransfusionBlood specimenBrazilCaringCell CommunicationChronicClinicalCollaborationsCollectionComplicationConsentDNADataDatabasesElectronic MailEnsureEnvironmentErythrocyte TransfusionErythrocytesEventFreezingGene ExpressionGenetic TranscriptionHealthcareHemoglobinopathiesHospitalsImmunizeIndividualInflammationInvestigationIsoantibodiesLabelLaboratoriesLeukocytesLinkMetadataOdds RatioParticipantPathway interactionsPatientsPediatric HospitalsPeripheral Blood Mononuclear CellPhenotypePhysiciansPopulationPositioning AttributeReportingResearchResearch PersonnelRiskRoleSamplingSampling StudiesSickle Cell AnemiaSiteSourceTelephoneTest ResultTestingTherapeutic InterventionTimeTrans-Omics for Precision MedicineTransfusionValidationVariantVenous blood samplingbiobankclinical applicationclinical materialclinical phenotypecohortexperienceexperimental studygenetic variantgenome analysisgenome sequencinghospital carehuman studyhuman subjectimmunogenicityinsightinterestmeetingsparticipant enrollmentpediatric patientsperipheral bloodprogramsprospectiveresponders and non-responderssingle-cell RNA sequencingtherapeutic developmenttranscriptometransfusion medicinewhole genome
项目摘要
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)同种异体免疫率显著较高
比其他接受输注供体红细胞的人群要多。根据研究、输血情况,
和环境,据报道,18-47%的SCD个体对RBC同种异体免疫,
输血后的抗原,也更有可能产生额外的同种抗体,
输血在急性SCD并发症的情况下输血的优势比高8-12倍(1),
导致同种抗体形成。我们假设我们会发现
通过一项大规模、无偏见的人体研究,整合受体组学和
环境条件(即,存在或不存在急性疾病和高水平炎症)
输血。我们将首先通过分析鉴定与同种免疫相关的变异来测试这一点。
基因组测序(WGS)的反应者和非反应者。我们假设患有SCD的个体
非洲遗产将具有与免疫原性增加相关的遗传变异。为了验证这一点,我们
分析我们的Emory SCD队列(n=2000)的WGS,这些队列在10年后有或没有产生同种抗体,
或更多的输血,并与TOPMed中REDSIII队列的WGS进行比较,
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
个体基线、输血时和输血后一个月时白细胞亚群的变化
患有SCD的患者是否发生同种异体免疫。我们假设,我们将确定基因的改变,
表达(和附属途径)与同种异体免疫相关。这将有立竿见影的好处
允许我们为同种免疫开发转录风险评分(TRS),如果
确定合理制定治疗干预措施的途径。最后,我们将评估
炎症反应。我们假设SCD患者的同种异体免疫发生在
急性炎症的发生机制不同于同种异体免疫
慢性输血或健康个体。我们将比较aim 2中获得的转录组与
scRNAseq数据从来自40名非SCD个体的队列的储存PBMC获得,所述非SCD个体发展为
Rh不匹配的RBC激发的同种抗体。我们预测我们的分析将使我们能够确定
个体在同种异体免疫发生前的风险,并阐明炎症在
同种免疫,在SCD患者和健康个体中。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Vivien Andrea Sheehan其他文献
Vivien Andrea Sheehan的其他文献
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{{ truncateString('Vivien Andrea Sheehan', 18)}}的其他基金
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 - 财政年份:2023
- 资助金额:
$ 66.42万 - 项目类别:
A Genomics Approach to Gamma-Globin Regulation
伽马珠蛋白调控的基因组学方法
- 批准号:
9164151 - 财政年份:2016
- 资助金额:
$ 66.42万 - 项目类别:
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