Complications of Hemolysis and Transfusion Therapy

溶血和输血治疗的并发症

基本信息

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
项目类别：
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

项目摘要

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.

总体摘要我们的项目重点是从机制上理解红血的有益和有害影响血红蛋白病患者的红细胞（RBC）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病理生理学的许多方面发挥着核心作用，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了与生俱来的关键的体液免疫细胞和造血生态位细胞对溶血作用敏感，血红素感应机制是输血反应的关键。该PPG的总体工作假设血红素超载会导致免疫系统反应改变和骨髓生态位失调。我们进一步认为，输血在溶血性疾病中的有效性取决于它们改变溶血状态的能力。促炎环境转为抗炎环境。建立在高度相互关联和协同的研究基础上由多学科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，包括同种免疫（项目 1）和血寄生虫感染（项目 2）至 ACS（项目 3）以及潜在的影响造血移植结果（项目 4）。具体来说，我们将专门探讨血红素途径在输血过程中对 B 细胞和 T 细胞进行检测，以检验溶血直接影响体液免疫的假设对输血的反应以及 DOCK8/ROS/HO-1 血红素途径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）。我们将研究血液寄生虫感染中旁观者溶血的机制，并检验以下假设：响应溶血和失调加剧而从抗炎状态转变为促炎状态红细胞生成可能是过度溶血状态的基础（项目 2）。以我们的数据为基础通过溶血调节先天免疫反应，我们将确定血红素诱导的相关性炎症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是否输血结果取决于巨噬细胞的抗炎代谢转换（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生态位和造血干/祖细胞，可以通过输血缓解（项目 4).行政核心将促进沟通并整合科学目标，并确保高维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本以及基于临床的见解，以促进和增强该技术的临床适用性本计划项目的调查结果。我们相信拟议的项目具有高度互动性和每个项目中开发的进步将对其他项目产生巨大价值。我们进一步相信，通过 PPG 机制我们的计划将全面了解输血如何影响机制血红蛋白病的关键血红素途径将为优化输血提供必要的框架对这些高度脆弱的患者群体的管理和支持。