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）输血是美国患者的最常见热方式， 每年有70名美国人中，大约有1个被输出。尽管加拿大皇家银行的输血挽救了生命，但 一些患者会针对供体RBC血组抗原产生同种抗体。临床意义 同种抗体在输血，妊娠和移植环境中具有不利影响。很少 一般来说 已经敏感的患者的同种抗体。那就是了解风险的临床需求未满足 可以识别（1）哪些RBC单位具有免疫原性的因素，以及（2）哪些患者有高风险 同种免疫；这些知识将导致预防和/或减轻这些不良事件的新型策略。 （1）捐赠者RBC单位和（2）输血接收者的免疫力可能会影响同种异体免疫风险 系统。从观察上，在反复献血者的RBC单位中观察到更高的网状细胞计数 因为补偿性网状细胞增多症的持续时间比捐赠之间的间隔更长。此外， 同种免疫风险最高风险的输血接受者也有持续的网状细胞增多症（例如，患有患者 溶血性贫血）。这，我们生成了可拖动的鼠模型，以测试网状细胞的假设 调节同种免疫率。在此，我们提供了强大的初步数据，以识别网状细胞为 RBC在供体和受体级别上的重大危险因素：较高的同种异体免疫力 含有高网状细胞计数的RBC供体单位后，可以看到速率/同种抗体水平 以及同种异体RBC输入表现出网状细胞增多症的受体。因为网状细胞不同 从成熟的RBC（例如，网状细胞具有线粒体），我们假设网状细胞包含和/或 表达激活免疫细胞并启动同种免疫反应的配体。我们使用两个临床前模型 以及人类的样品以阐明网状细胞介导的基础机制增强 同种免疫。为此，我们开发了4种鼠模型来研究反映人类环境的网状细胞 （例如，溶血性贫血，重复的静脉切开术），因为不同类型的压力红细胞生成可能会导致 网状细胞差异。为了阐明网状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RBC单元中对网状细胞的免疫反应的方法和/或 输血接受者的诱导。为了将我们的发现转化为人类，我们还将研究网状细胞 调节从网状细胞增多症患者（例如溶血性贫血）中收集的B细胞的功能 与健康对照相比。阐明网状细胞如何增强同种异体免疫（1）有助于识别 潜在的免疫原性供体RBC单位和（2）预测哪些输血受者的风险更高 开发同种抗体；这些将共同防止未来的同种免疫事件。另外，这个 知识将提供有关预防和/或治疗同种免疫的潜在治疗靶标的见解。