Immune Pathophysiology of Sickle Cell Disease

镰状细胞病的免疫病理生理学

• 批准号: 10579970
• 负责人: Karina Yazdanbakhsh
• 金额: $ 92.04万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2028-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579970
• 关键词: Affect; Alloimmunization; Area; Biological Models; Cells; Chronic; Clinical; Development; Disease; Drug Metabolic Detoxication; Endothelium; Enzymes; Event; Experimental Models; Functional disorder; Goals; Heme; Hemolysis; Immune; Immune response; In Vitro; Inflammatory; Innate Immune Response; Isoantibodies; Knowledge; Laboratories; Leukocytes; Life; Mission; Molecular; National Heart, Lung, and Blood Institute; Pain; Pathway interactions; Patients; Reaction; Research; Role; Sampling; Sickle Cell; Sickle Cell Anemia; Transfusion; blood product; cell type; heme oxygenase-1; human model; in vivo; interest; monocyte; mouse model; novel; novel therapeutics; patient population; prevent; programs; protective pathway; therapeutic target

Project Abstract A chronic inflammatory state is now considered a hallmark of sickle cell disease (SCD) resulting from ongoing hemolytic insult to the underlying vasculature and repeated cycles of vaso-occlusion crisis (VOC). Transfusions remain a cornerstone treatment for patients with SCD, but unlike other transfused patient populations, a higher proportion (20-50%) of patients with SCD develop alloantibodies with potentially life-threatening sequalae. These include poorly understood delayed transfusion reactions (DHTRs) whose occurrence, as well as clinical progression from mild to severe, is unpredictable. A long-standing interest of our research program has been to understand the underling immune mechanisms leading to SCD complications including VOC and transfusion complications. Our studies have uncovered an underappreciate role of circulating monocytes and the innate immune response to hemolysis, a hallmark of SCD, in transfusion complications including alloimmunization and DHTRs. Our projected studies as part of this R35 will be focused on innate immune cellular pathways that magnify the inflammatory SCD state versus the cells' heme protective pathways such as the heme detoxifying key enzyme heme oxygenase 1 in alloimmunization and in the development of DHTRs. Our laboratory has also identified a novel function for a subset of circulating monocytes, referred to as patrolling monocytes (PMo), in their ability to scavenge and remove damaged endothelium and endothelial-attached sickle RBCs. The discovery of a novel mechanism of action of PMo in SCD offers a paradigm shift in our understanding of VOC and opens up the possibility that PMos can be manipulated to prevent painful VOC. An objective of the proposed studies in this R35 is to understand the mechanisms by which PMo protect SCD vasculature and how they are affected both functionally and numerically during a vaso-occlusive event with the goal to help establish their role in VOC pathophysiology, and their potential as a therapeutic target for VOC. As we have done in the past, all the proposed studies for both objectives will combine the use of in vivo mouse models, in vitro human model systems, and patient samples to mechanistically dissect in a rigorous manner how specific immune cell types and molecular pathways contribute to SCD alloimmunization and VOC. Altogether, we believe that our laboratory's approach of integrating studies in humans and experimental models to mechanistically dissect immune pathways that regulate SCD complications is likely to be impactful and generate novel findings in areas critical to the NHLBI scientific mission.

项目摘要 慢性炎症状态现在被认为是镰状细胞病（SCD）的标志，其由持续的炎症反应引起。 对血管系统的溶血性损伤和反复循环的血管闭塞危象（VOC）。输血 仍然是SCD患者的基础治疗，但与其他输血患者人群不同， 一部分（20-50%）SCD患者产生具有潜在危及生命后遗症的同种抗体。这些 包括对延迟性输血反应（DHTR）知之甚少， 从轻度到重度的进展是不可预测的。我们的研究项目的一个长期兴趣是 了解导致SCD并发症（包括VOC和输血）的潜在免疫机制 并发症我们的研究揭示了循环单核细胞和先天性巨噬细胞的作用 溶血的免疫反应，SCD的标志，在输血并发症，包括同种免疫和 DHTR。作为R35的一部分，我们计划的研究将集中在先天免疫细胞通路上， 放大炎症SCD状态与细胞的血红素保护途径，如血红素解毒 血红素加氧酶1是同种异体免疫和DHTR发展中的关键酶。我们的实验室也 确定了循环单核细胞亚群的一种新功能，称为巡逻单核细胞（PMo）， 它们抑制和清除受损内皮和内皮附着镰状红细胞的能力。发现 PMo在SCD中的一种新的作用机制的研究为我们对VOC的理解提供了一个范式转变， 增加了PMO可以被操纵以防止疼痛的VOC的可能性。拟议研究的一个目标是， 该R35旨在了解PMo保护SCD血管系统的机制以及它们如何受到影响 在血管闭塞事件期间的功能和数值，目的是帮助确定它们在VOC中的作用 病理生理学，以及它们作为VOC治疗靶点的潜力。正如我们过去所做的那样， 针对这两个目标的拟议研究将联合收割机使用体内小鼠模型、体外人模型 系统和患者样本，以严格的方式机械地剖析特定的免疫细胞类型 分子途径参与SCD同种免疫和VOC。总的来说，我们相信， 实验室的方法，整合在人类和实验模型的研究，以机械解剖 调节SCD并发症的免疫途径可能具有影响力，并在以下领域产生新的发现： 对NHLBI的科学使命至关重要。