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.

对于大量需要 输血（仅在美国，每年有70人中有70人（约5,000,000名患者））。虽然 在多种环境中输血的障碍，同种免疫尤其对镰状细胞患者尤其有问题 疾病（SCD）是由于1）同种免疫的率提高（高达30％），2）需要慢性输血， 3）未发现（或新的）同种抗体的风险会引起潜在的灾难性的过度分解。有 很少有有效的治疗干预措施可以防止RBC同种免疫化（例如，广泛的抗原匹配）。 对于所有输血的指示，患者往往是随着时间的流逝而形成同种抗体的“反应者” 即使经过多次输血，也没有可检测到的同抗体的持续输血或“无反应者”。 目前，我们无法预测哪些患者可能是反应者并被同种免疫。这个P01 专注于解决大量患者的RBC同种免疫的持续问题 需要输血，并有同种免疫的风险。该程序是围绕中心核心（核心）结构的 a）将从2000名SCD患者的队列中收集纵向样本（处于稳态时， 输血和转交后一个月）与详细的临床信息有关，包括RBC 同种免疫。项目1-3将新颖的翻译鼠模型与核心A的临床样品结合在一起 虽然项目4使用核心A的样本通过基于OMICS的方法来检验假设并生成 项目1-3中研究途径的数据。这样，提议的程序创造了方法的协同作用 具有将鼠的发现转化为人类的能力，并在小鼠中建模人类发现。使用样品 从核心A作为公共资源，提出了四个项目。项目1以新颖的观察为基础 SLE的小鼠模型概括了在患有SLE的人类中观察到的RBC同种免疫的增加 来自核心A的模型和样品测试TLR7，TLR9和抗核酸抗体的机械作用 在RBC同种免疫中。项目2建立在我们的新颖观察结果上，即多个嘌呤能信号通路 调节小鼠中的RBC同种异体免疫化，并利用鼠标模型，样品形成核心A来测试 CD73，AMP，Adora1，腺苷和Adora2b在RBC同种免疫中的机械作用。项目3建议 在临床前模型和人类研究中，机械驱动的研究扩展了我们的新发现 网状细胞（在供体RBC单位或输血接受者中）是RBC同种免疫的危险因素。项目 4将调查通过分析给定SCD患者的潜在遗传危险因素 整个基因组测序以及通过同种免疫的特定分子驱动器通过 分析单细胞RNASEQ数据。该P01旨在具有指导临床实践的近期益处 通过发现响应者/非响应者患者的预测因子以及阐明的长期益处 RBC同种免疫的机制允许理性靶标进行治疗。