Complications of Hemolysis and Transfusion Therapy

溶血和输血治疗的并发症

• 批准号: 10220124
• 负责人: Karina Yazdanbakhsh
• 金额: $ 312.15万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220124
• 关键词: Acute; Affect; Alloimmunization; Anemia; Anti-Inflammatory Agents; B cell differentiation; B-Cell Development; B-Lymphocytes; Babesia; Babesiosis; Binding; Biological; Bone Marrow; CFU-E; Cells; Chronic; Clinical; Collaborations; Communication; Data; Defect; Development; Disease; Disease model; Effectiveness; Effector Cell; Erythroblasts; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythropoiesis; Exhibits; Exposure to; Functional disorder; Goals; Hematopoietic; Hematopoietic stem cells; Heme; Hemoglobin; Hemoglobinopathies; Hemolysis; Hemolytic Anemia; Human; Immune; Immune response; Impairment; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Innate Immune Response; Iron; Island; Knowledge; Life; Lung; Mediator of activation protein; Mesenchymal Stem Cells; Metabolic; Metabolic Pathway; Methods; Molecular; Monitor; Mus; Outcome; Output; Oxidative Stress; Pathway interactions; Patients; Phenotype; Play; Prevention; Productivity; Protocols documentation; Quinine; Reaction; Regulation; Research Project Grants; Risk; Role; Sampling; Seminal; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Sputum; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transfusion; Transplantation; Viscosity; acute chest syndrome; base; cell type; clinical application; extracellular vesicles; heme 1; human subject; in vivo Model; infection rate; inflammatory milieu; insight; iron metabolism; macrophage; metabolome; mouse model; multidisciplinary; patient population; prevent; progenitor; programs; response; sickling; small molecule; synergism; targeted agent; uptake; vascular endothelial dysfunction

Overall Abstract Our Program Project focuses on mechanistic understanding of the beneficial and harmful effects of red blood cell (RBC) transfusions in patients with hemoglobinopathies. Increasing evidence suggest that free hemoglobin and heme play central roles in many aspects of the pathophysiology of hemolytic anemias, especially in SCD, causing vascular endothelial dysfunction, inflammation, and oxidative stress. Our Team has shown that innate and key humoral immune cells and hematopoietic niche cells are sensitive to the effects hemolysis and that heme-sensing mechanisms are key to the response to transfusions. The overall working hypothesis of this PPG is that heme overload leads to altered immune system response and a dysregulated bone marrow niche. We further posit that effectiveness of transfusions in hemolytic disorders depends on their ability to switch the proinflammatory to an anti-inflammatory environment. Building on highly inter-related and synergistic research projects led by a group of multidisciplinary local experts, including a highly promising ESI, we will interrogate the impact of hemolysis and outcome of transfusions on complications associated with SCD, ranging from alloimmunization (Project 1) and infections of hemoparasites (Project 2) to ACS (Project 3) and potentially affecting hematopoietic transplant outcomes (Project 4). Specifically, we will probe heme pathways specifically in B and T cells during transfusions to test the hypothesis that hemolysis directly affects humoral immune response to transfusions and that altered DOCK8/ROS/HO-1 heme pathways dictate alloimmunization risk and even bystander hemolysis associated with life-threatening delayed hemolytic transfusion reactions (Project 1). We will examine mechanisms of bystander hemolysis in hemoparasite infections and test the hypothesis that the switch from anti- to proinflammatory states in response to hemolysis and exacerbation of dysregulated erythropoiesis may underlie the exaggerated hyperhemolytic state (Project 2). Building on our data on modulation of innate immune response by hemolysis, we will determine the relevance of heme-induced inflammatory macrophage in the development of the debilitating sickle acute chest syndrome and whether transfusion outcomes are dependent on an anti-inflammatory metabolic switch in macrophages (Project 3). We will also test the hypothesis that the proinflammatory effects of free heme leads to dysfunction of the bone marrow hematopoietic niche and hematopoietic stem/progenitor cells, which can be alleviated by transfusions (Project 4). An Administrative Core will facilitate communication and integrate scientific goals and assure that high scientific productivity standards are maintained. The Human Subject Core will provide clinically annotated biological samples as well as clinically based insights to facilitate and enhance the clinical applicability of the findings emerging from this Program Project. We believe that the proposed Projects are highly interactive and that advances developed within each will have great value to other Projects. We further believe that through a PPG mechanism our Program will achieve a comprehensive mechanistic understanding how transfusions impact key heme pathways in hemoglobinopathies will provide the necessary framework for optimization of transfusion management and support for these highly vulnerable patient population.

总体摘要 我们的计划项目的重点是红血的有益和有害影响的机械理解 血红蛋白病患者的红细胞输注。越来越多的证据表明游离血红蛋白 和血红素在溶血性贫血的病理生理学的许多方面，特别是在SCD中， 引起血管内皮功能障碍、炎症和氧化应激。我们的团队已经证明， 关键体液免疫细胞和造血小生境细胞对溶血作用敏感， 血红素感应机制是对输血反应的关键。本PPG的总体工作假设 血红素超载导致免疫系统反应改变和骨髓生态位失调。 我们进一步证实，输血在溶血性疾病中的有效性取决于它们转换溶血性疾病的能力。 从促炎到抗炎的环境。建立在高度相互关联和协同增效的研究基础上 由一组多学科的当地专家领导的项目，包括一个非常有前途的ESI，我们将询问 溶血和输血结果对SCD相关并发症的影响， 同种免疫（项目1）和血液寄生虫感染（项目2）到ACS（项目3），并可能 影响造血移植结果（项目4）。具体来说，我们将专门探测血红素途径 在输血过程中的B和T细胞，以测试溶血直接影响体液免疫的假设， 对输血的反应和DOCK 8/ROS/HO-1血红素通路的改变决定了同种免疫风险， 甚至与危及生命的迟发性溶血性输血反应相关的旁观者溶血（项目1）。 我们将研究寄生虫感染中旁观者溶血的机制，并检验以下假设： 从抗炎状态到促炎状态的转换是对溶血和失调的恶化的反应， 红细胞生成可能是过度溶血状态的基础（项目2）。根据我们的数据， 通过溶血调节先天免疫应答，我们将确定血红素诱导的 炎性巨噬细胞在衰弱性镰状急性胸部综合征的发展中的作用以及 输血结果取决于巨噬细胞中的抗炎代谢开关（项目3）。我们 还将检验游离血红素的促炎作用导致骨髓功能障碍的假设 造血小生境和造血干/祖细胞，这可以通过输血缓解（项目 4）。一个行政核心将促进沟通，整合科学目标，并确保高水平的 保持科学的生产力标准。人类受试者核心将提供临床注释 生物样品以及基于临床的见解，以促进和增强的临床适用性， 从这个项目中发现的问题。我们认为，拟议项目具有高度互动性， 每个项目的进展将对其他项目产生巨大价值。我们进一步认为，通过 PPG机制我们的计划将全面了解输血如何影响 血红蛋白病中的关键血红素途径将为优化输血提供必要的框架 管理和支持这些高度脆弱的患者群体。