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.

对输注的红细胞的同种异体免疫仍然是大量需要免疫的患者的主要问题。 输血（仅在美国，每年约70人中有1人（约5，000，000例患者））。虽然 在多种情况下，同种免疫对镰状细胞患者尤其成问题， 疾病（SCD）由于1）同种免疫率增加（高达30%），2）需要慢性输血， 和3）未检测到的（或新的）同种抗体引起潜在的灾难性高溶血的风险。有 很少有有效的治疗干预来预防RBC同种免疫（例如，广泛抗原匹配）。 对于所有输血适应症，患者往往是“反应者”，随着时间的推移会产生同种抗体， 正在进行的输血或即使在多次输血后也没有可检测到的同种抗体的“无应答者”。 目前，我们无法预测哪些患者可能成为应答者并成为同种免疫。P01 重点是解决红细胞同种免疫的长期问题，为大量的患者， 需要输血并有同种免疫的风险。该计划是围绕一个中央核心（核心 A）将从2000名SCD患者的队列中收集纵向样本（在稳态下， 输血和输血后1个月）与详细临床信息（包括RBC）相关 同种免疫项目1-3联合收割机将新型转译小鼠模型与来自核心A的临床样品相结合 而项目4使用核心A的样本通过基于组学的方法来测试假设，并生成 项目1-3中研究的路径数据。通过这种方式，拟议的方案创造了一种协同增效的方法， 能够将小鼠的发现转化为人类，并在小鼠中模拟人类的发现。使用样品 从核心A作为共同资源，提出了四个项目。项目1建立在一个新的观察基础上， SLE的小鼠模型重现了在患有SLE的人类中观察到的增加的RBC同种异体免疫， 来自核心A的模型和样品，以测试TLR 7、TLR 9和抗核酸抗体的机制作用 RBC同种异体免疫。项目2建立在我们的新观察基础上， 调节小鼠中的RBC同种免疫，并利用小鼠模型和来自核心A的样品来测试 CD 73、AMP、Adora 1、腺苷和Adora 2b在RBC同种免疫中的机制作用。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（在供体RBC单位或输血受体中）是RBC同种免疫的风险因素。项目 4将调查潜在的遗传风险因素，使一个给定的患者与SCD通过分析， 全基因组测序和特定的分子驱动程序的同种异体免疫接种到一个给定的输血， 单细胞RNASeq数据的分析。本P01旨在具有指导临床实践的近期受益 通过发现应答者/非应答者患者的预测因子以及阐明 红细胞同种免疫机制，为治疗开发提供合理的目标。