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，该病是由持续的炎症引起的。 对底层脉管系统的溶血损伤和血管闭塞危机（VOC）的反复循环。输血 仍然是 SCD 患者的基石治疗，但与其他输血患者群体不同，更高的 比例（20-50%）的 SCD 患者会产生具有潜在危及生命的后遗症的同种抗体。这些 包括人们知之甚少的延迟输血反应 (DHTR)，其发生情况以及临床情况 从轻微到严重的进展是不可预测的。我们研究计划的长期兴趣是 了解导致 SCD 并发症的潜在免疫机制，包括 VOC 和输血 并发症。我们的研究发现循环单核细胞和先天性的作用被低估了。 对溶血的免疫反应是 SCD 的一个标志，在输血并发症中包括同种免疫和 DHTR。作为 R35 的一部分，我们预计的研究将集中于先天免疫细胞途径， 放大炎症性 SCD 状态与细胞血红素保护途径（例如血红素解毒）的关系 同种免疫和 DHTR 发育中的关键酶血红素加氧酶 1。我们实验室还 确定了循环单核细胞子集的一种新功能，称为巡逻单核细胞（PMo）， 它们清除和去除受损内皮和内皮附着的镰状红细胞的能力。发现 PMo 在 SCD 中的一种新作用机制的研究为我们对 VOC 的理解提供了范式转变，并开启了 提高了可以操纵 PMo 来预防痛苦的 VOC 的可能性。拟议研究的目标 此 R35 旨在了解 PMo 保护 SCD 脉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从功能和数量上进行评估，目的是帮助确立其在 VOC 中的作用 病理生理学，及其作为 VOC 治疗靶点的潜力。正如我们过去所做的那样，所有 针对这两个目标的拟议研究将结合使用体内小鼠模型和体外人类模型 系统和患者样本，以严格的方式机械地剖析特定免疫细胞类型如何 分子途径有助于 SCD 同种免疫和 VOC。总而言之，我们相信我们的 实验室将人体研究和实验模型结合起来进行机械解剖的方法 调节 SCD 并发症的免疫途径可能会产生影响并在一些领域产生新的发现 对 NHLBI 的科学使命至关重要。