Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion

红细胞输注同种免疫的基本机制和转化机制

• 批准号: 10711666
• 负责人: JAMES C. ZIMRING
• 金额: $ 243.08万
• 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/10711666
• 关键词: ADORA1 gene; ADORA2B gene; Acute; Address; Adenosine; Alloantigen; Alloimmunization; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biology; Blood; Blood Group Antigens; Blood Transfusion; Chronic; Clinical; Collection; Data; Databases; Erythrocyte Transfusion; Erythrocytes; Gene Expression; Gene Expression Profile; Genetic Determinism; Genetic Polymorphism; Goals; Human; Immunize; Immunology; Individual; Inflammation; Interferon alpha; Isoantibodies; Life; Link; Methods; Mitochondria; Modeling; Modification; Molecular; Monitor; Mus; Nucleic Acids; Pathology; Pathway interactions; Patients; Pattern; Persons; Phenotype; Population; Pre-Clinical Model; Predisposing Factor; Production; Purinoceptor; Regulation; Research; Resources; Reticulocytes; Risk; Risk Factors; Role; Sampling; Sickle Cell Anemia; Signal Induction; Signal Pathway; Signal Transduction; Specimen; Structure; Systemic Lupus Erythematosus; TLR7 gene; Technology; Testing; Therapeutic Intervention; Time; Transfusion; Translating; antagonist; clinical practice; cohort; cytokine; design; ecto-nucleotidase; experimental study; gain of function; genetic risk factor; genetic variant; genome sequencing; human model; human study; human subject; immunoreaction; innate immune pathways; mouse model; novel; novel therapeutics; prevent; programs; response; single cell analysis; single-cell RNA sequencing; synergism; targeted treatment; therapeutically effective; therapy development; transcriptome; transcriptomics; translational genomics; translational model; whole genome

Alloimmunization to transfused RBCs remains a major problem for the large number of patients who require transfusion (approximately 1 out of 70 people (~5,000,000 patients) annually in the USA alone). Although a barrier to transfusion in multiple settings, alloimmunization is particularly problematic for patients with sickle cell disease (SCD) due to 1) the increased rate of alloimmunization (up to 30%), 2) the need for chronic transfusion, and 3) the risk of undetected (or new) alloantibodies causing potentially catastrophic hyperhemolysis. There are very few effective therapeutic interventions to prevent RBC alloimmunization (e.g., extensive antigen matching). For all transfusion indications, patients tend to be either “responders” that develop alloantibodies over time with ongoing transfusion or “non-responders” with no detectable alloantibodies even after many transfusions. Currently, we cannot predict which patients are likely to be responders and become alloimmunized. This P01 focuses on addressing the persistent problem of RBC alloimmunization for the large number of patients who require transfusions and are at risk for alloimmunization. The program is structured around a central core (Core A) that will collect longitudinal samples from a cohort of 2000 patients with SCD (at steady state, at time of transfusion, and one-month post-transfusion) linked to detailed clinical information, including RBC alloimmunization. Projects 1-3 combine novel translational murine models with clinical samples from Core A while Project 4 uses samples from Core A to test hypotheses through an omics-based approach and generates data on pathways studied in Projects 1-3. In this way, the proposed program creates a synergy of approaches with the ability to translate murine findings into humans and model human findings in mice. Using the samples from Core A as a common resource, four projects are proposed. Project 1 builds on a novel observation that a mouse model of SLE recapitulates increased RBC alloimmunization observed in humans with SLE and utilizes the model and samples from Core A to test the mechanistic role of TLR7, TLR9 and anti-nucleic acid antibodies in RBC alloimmunization. Project 2 builds on our novel observation that multiple purinergic signaling pathways regulate RBC alloimmunization in mice and utilizes mouse models and samples form Core A to test the mechanistic role of CD73, AMP, Adora1, adenosine and Adora2b in RBC alloimmunization. Project 3 proposes mechanistically driven studies in pre-clinical models and human studies to expand upon our novel finding that reticulocytes (in donor RBC units or in transfusion recipients) are a risk factor for RBC alloimmunization. Project 4 will investigate the underlying genetic risk factors that predispose a given patient with SCD through analysis of whole genome sequencing and the specific molecular drivers of alloimmunization to a given transfusion through analysis of single cell RNASeq data. This P01 is designed to have near-term benefits of guiding clinical practice by discovering predictors of responder/non-responder patients and longer-term benefits of elucidating mechanisms of RBC alloimmunization to allow rational targets for therapy development.

对于大量患者来说，输血红细胞的异基因免疫仍然是一个主要问题，他们需要 输血(仅在美国，每年每70人中约有1人(约500万患者)输血)。尽管一个 在多个环境中，异基因免疫对于镰状细胞患者来说尤其成问题 疾病(SCD)的原因是1)异基因免疫率增加(高达30%)，2)需要长期输血， 以及3)未检测到的(或新的)同种异体抗体导致潜在的灾难性溶血的风险。确实有 预防红细胞同种异体免疫的有效治疗干预措施很少(例如，广泛的抗原匹配)。 对于所有的输血适应症，患者往往是随着时间的推移而产生同种异体抗体的“应答者” 持续输血或“无反应者”，即使在多次输血后仍未检测到同种异体抗体。 目前，我们无法预测哪些患者可能成为应答者并获得同种免疫。本P01 重点解决大量患者的红细胞同种异体免疫的长期问题 需要输血，并面临同种免疫的风险。该计划围绕一个中央核心(Core)构建 A)将从2000名SCD患者队列中收集纵向样本(处于稳定状态，在 输血和输血后一个月)与包括RBC在内的详细临床信息相联系 同种异体免疫。项目1-3将新的翻译小鼠模型与核心A的临床样本相结合 而项目4使用核心A的样本通过基于组学的方法测试假设，并生成 关于项目1-3中研究的路径的数据。通过这种方式，拟议的计划创造了一种方法的协同 有能力将老鼠的发现转化为人类，并在小鼠身上模拟人类的发现。使用样本 从核心A这一公共资源出发，提出了四个项目。项目1建立在一个新的观察结果的基础上 一种系统性红斑狼疮小鼠模型概括了在人类系统性红斑狼疮中观察到的红细胞同种异体免疫增加，并利用 检测TLR7、TLR9和抗核酸抗体作用机制的模型和A核心样本 在红细胞同种异体免疫中。项目2建立在我们新观察到的多条嘌呤能信号通路的基础上 调节小鼠红细胞同种免疫，并利用小鼠模型和核心A的样本来测试 CD73、AMP、Adora1、腺苷和Adora2b在红细胞同种异体免疫中的作用项目3建议 临床前模型和人体研究中的机械驱动研究，以扩展我们的新发现 网织红细胞(供者红细胞单位或输血受者)是红细胞同种异体免疫的危险因素。项目 4将通过分析以下因素来调查导致特定SCD患者的潜在遗传风险因素 全基因组测序和对特定输血的同种免疫的特定分子驱动因素 单细胞RNAseq数据分析。P01的设计目的是为了指导临床实践的近期好处 通过发现应答者/无应答者患者的预测因素和阐明的长期好处 红细胞同种异体免疫的机制，以允许治疗发展的合理靶点。