Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion. Project 3

红细胞输注同种免疫的基本和转化机制。

• 批准号: 10711670
• 负责人: Krystalyn E Hudson
• 金额: $ 48.78万
• 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/10711670
• 关键词: Adherence; Adverse effects; Adverse event; Allogenic; Alloimmunization; American; Anemia; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Autologous; B-Lymphocytes; Blood Group Antigens; Blood Transfusion; Blood donor; CD36 gene; Cells; Circulation; Clinical; Collecting Cell; Consumption; Data; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythropoiesis; Event; Exhibits; Future; General Population; Generations; Goals; Hemolytic Anemia; Hemorrhage; Hospitalization; Human; Immune; Immune response; Immune system; In Vitro; Innate Immune Response; Integrin alpha4beta1; Isoantibodies; Knowledge; Lesion; Life; Ligands; Measures; Mediating; Methods; Mitochondria; Modality; Mus; Organelles; Pathway interactions; Patient Care; Patients; Phenotype; Population; Pre-Clinical Model; Pregnancy; Production; Reaction; Resources; Reticulocyte count; Reticulocytes; Reticulocytosis; Risk; Risk Factors; Sampling; Sickle Cell Anemia; Stress; Surface Antigens; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Therapeutic procedure; Transfusion; Transgenic Organisms; Translating; Transplantation; Trauma; Vascular blood supply; Venous blood sampling; adaptive immune response; clinically significant; design; differential expression; high risk; immunogenic; immunogenicity; improved; insight; knockout animal; mouse model; novel; novel strategies; novel therapeutic intervention; patient population; premature; prevent; response; screening; targeted treatment; therapeutic target; therapeutically effective

Red blood cell (RBC) transfusion is the most common therapeutic modality given to patients in America, with approximately 1 out of every 70 Americans being transfused each year. Although RBC transfusions save lives, some patients develop alloantibodies against donor RBC blood group antigens. Clinically significant alloantibodies have adverse effects in transfusion, pregnancy, and transplant settings. There are very few effective therapeutic interventions to prevent RBC alloimmunization, in general, and/or to eliminate alloantibodies in already sensitized patients. Thus, there is an unmet clinical need to understand the risk factors that can identify (1) which RBC units are immunogenic and (2) which patients are at high risk for alloimmunization; this knowledge will lead to novel strategies to prevent and/or alleviate these adverse events. Alloimmunization risk may be impacted by (1) the donor RBC unit and (2) the transfusion recipient’s immune system. Observationally, higher reticulocyte counts are observed in RBC units from repeat blood donors because compensatory reticulocytosis lasts longer than the interval between donations. Additionally, transfusion recipients at highest risk of alloimmunization also have ongoing reticulocytosis (e.g., patients with hemolytic anemias). Thus, we generated tractable murine models to test the hypothesis that reticulocytes modulate alloimmunization rates. Herein, we provide robust preliminary data that identify reticulocytes as a significant risk factor for RBC alloimmunization at both the donor and recipient levels: higher alloimmunization rates/alloantibody levels are seen upon transfusion of RBC donor units containing high reticulocyte counts as well as upon allogeneic RBC transfusion into recipients exhibiting reticulocytosis. Because reticulocytes differ from mature RBCs (e.g., reticulocytes have mitochondria), we hypothesize that reticulocytes contain and/or express ligands that activate immune cells and initiate alloimmune responses. We use both pre-clinical models and samples from humans to elucidate the mechanisms underlying reticulocyte-mediated enhanced alloimmunization. To that end, we developed 4 murine models to study reticulocytes that reflect human settings (e.g., hemolytic anemia, repetitive phlebotomy) as different types of stress erythropoiesis may result in reticulocyte differences. To elucidate how reticulocytes enhance alloantibodies, we will leverage sophisticated methods to identify, track, and measure immune responses to reticulocytes in an RBC unit and/or upon their induction in a transfusion recipient. To translate our findings to humans, we will also study how reticulocytes modulate the function of B cells collected from patients with reticulocytosis (e.g., hemolytic anemia) as compared to healthy controls. Elucidating how reticulocytes enhance alloimmunization will (1) aid in identifying potentially immunogenic donor RBC units and (2) predict which transfusion recipients are at higher risk of developing alloantibodies; together these will prevent future alloimmunization events. Additionally, this knowledge will provide insights into potential therapeutic targets to prevent and/or treat alloimmunization.

红细胞（RBC）输注是美国患者最常见的治疗方式， 大约每70个美国人中就有一个每年输血。虽然红细胞输血可以挽救生命， 一些患者产生针对供体RBC血型抗原的同种抗体。临床意义 同种抗体在输血、妊娠和移植环境中具有副作用。很少有 有效的治疗干预，以防止红细胞同种免疫，一般来说，和/或消除 已致敏患者的同种抗体。因此，了解风险的临床需求尚未得到满足 可以识别（1）哪些RBC单位具有免疫原性和（2）哪些患者具有高风险的因素 同种异体免疫;这方面的知识将导致新的策略，以防止和/或减轻这些不良事件。 同种异体免疫风险可能受到（1）供体RBC单位和（2）输血受体免疫的影响。 系统从观察上看，重复献血者的RBC单位中网织红细胞计数较高 因为代偿性网织红细胞增多症持续的时间比献血间隔时间长。此外，本发明还 同种免疫风险最高的输血接受者也具有持续的网织红细胞增多症（例如，患者 溶血性贫血）。因此，我们建立了易于处理的小鼠模型来检验网织红细胞 调节同种免疫率。在此，我们提供了可靠的初步数据，将网织红细胞鉴定为 在供体和受体水平上RBC同种免疫的显著风险因素：较高的同种免疫 在输注含有高网织红细胞计数的RBC供体单位时，观察到比率/同种抗体水平， 以及同种异体红细胞输注到表现出网织红细胞增多症的受者中。因为网织红细胞 来自成熟RBC（例如，网织红细胞具有线粒体），我们假设网织红细胞含有和/或 表达激活免疫细胞并启动同种免疫应答的配体。我们使用两种临床前模型 和来自人类的样本，以阐明网织红细胞介导的增强 同种免疫为此，我们开发了4种小鼠模型来研究反映人类环境的网织红细胞 (e.g.,溶血性贫血、反复放血），因为不同类型的应激性红细胞生成可能导致 网织红细胞差异。为了阐明网织红细胞如何增强同种抗体，我们将利用复杂的 识别、跟踪和测量对RBC单位中的网织红细胞和/或其 输血接受者的诱导。为了将我们的发现应用于人类，我们还将研究网织红细胞如何 调节从患有网织红细胞增多症的患者收集的B细胞的功能（例如，溶血性贫血） 与健康对照组相比。阐明网织红细胞如何增强同种异体免疫将（1）有助于识别 潜在免疫原性供体RBC单位和（2）预测哪些输血受体具有更高的 产生同种抗体;这些将共同防止未来的同种免疫事件。而且这个 知识将提供对潜在治疗靶点的深入了解，以预防和/或治疗同种免疫。