In vivo Monitoring of Neutrophil Function in Patients after Stem Cell Transplant

干细胞移植后患者中性粒细胞功能的体内监测

• 批准号: 10679553
• 负责人: Daniel Irimia
• 金额: $ 81.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-13 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679553
• 关键词: Acceleration; Address; Antifungal Agents; Azoles; Biological Markers; CSF3 gene; Candida; Candida albicans; Candida auris; Candidiasis; Cells; Communication; Diagnosis; Early Diagnosis; Effectiveness; Engineering; Enrollment; Functional disorder; Fungal Drug Resistance; Future; Goals; Growth; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hospitalization; Human; Hyphae; Image; Imaging Techniques; Immune response; In Vitro; Individual; Infection; Injury; Knowledge; Label; Leukocytes; Life; Malignant Neoplasms; Measurement; Measures; Microscopic; Molecular; Monitor; Morbidity - disease rate; Mycoses; Outcome; Patients; Performance; Phagocytosis; Population; Predisposition; Procedures; Prophylactic treatment; Recovery; Research; Resistance; Risk; Risk Estimate; Risk Factors; Risk Reduction; Role; Site; Stem cell transplant; Techniques; Therapeutic; Time; Transplant Recipients; Transplantation; accurate diagnosis; candidemia; chemokine; cytokine; design; first responder; functional restoration; fungus; high risk; human imaging; improved; improved outcome; in vivo; in vivo monitoring; infection risk; leukemia; mortality; neutrophil; novel imaging technology; patient stratification; post-transplant; restoration; tissue injury; tool

Hematopoietic stem cell transplant (HSCT), an essential procedure in the treatment of patients with hematological malignancies, also temporarily increases the risk for infections with invasive fungi. The recovery in the neutrophil number after HSCT is commonly regarded as a key metric for the restoration of antifungal defenses. However, the metric is imprecise, and there is an urgent need for new biomarkers to help identify the patients at risk. In the absence of new tools, the management of invasive fungal infections remains remarkably challenging. The long-term goal of this research is to engineer new tools and validate new metrics estimating the risk for invasive fungal infections in HSCT patients. Achieving this goal requires a focus on neutrophil swarming function, which is critical in effective antifungal immune responses. Swarming is distinct from phagocytosis in that it involves neutrophil-neutrophil communication that helps coordinate the activities of multiple cells toward blocking the growth of invasive fungi. The focus on neutrophil swarming is justified by preliminary results showing that in HSCT patients, even when the neutrophil count recovered at 4 weeks after transplant, a neutrophil swarming deficiency is still present and is substantial. Knowledge about how neutrophil swarming deficiency is resolved over time after HSCT is currently lacking. To address this knowledge gap and evaluate the utility of new biomarkers we will pursue the following specific aims: 1) Determine neutrophil swarming parameters that are distinct in healthy and HSCT patients. 2) Determine what cytokines help restore the swarming activity of neutrophils from HSCT patients and 3) Design new imaging techniques for label-free tracking of human neutrophils responding to microscopic tissue injuries in vivo. If successful, the proposed research could have a major impact on the lives of HSCT patients by improving the monitoring of their recovery and by identifying potential strategies for accelerating the recovery of their neutrophil functions and improving their protection against fungal infections.

造血干细胞移植（HSCT）是治疗患有白血病的患者的重要程序 血液系统恶性肿瘤也会暂时增加侵入性真菌感染的风险。复苏 HSCT后的中性粒细胞数量通常被认为是抗真菌药物恢复的关键指标 防御。然而，该指标并不精确，迫切需要新的生物标志物来帮助识别 处于危险中的患者。在缺乏新工具的情况下，侵袭性真菌感染的管理仍然非常困难 具有挑战性的。这项研究的长期目标是设计新工具并验证新指标估计 HSCT 患者发生侵袭性真菌感染的风险。实现这一目标需要关注中性粒细胞 集群功能，这对于有效的抗真菌免疫反应至关重要。蜂拥而至不同于 吞噬作用，因为它涉及中性粒细胞之间的通讯，有助于协调吞噬细胞的活动 多个细胞阻止入侵真菌的生长。对中性粒细胞聚集的关注是合理的 初步结果显示，在 HSCT 患者中，即使中性粒细胞计数在 4 周后恢复， 移植后，中性粒细胞聚集缺陷仍然存在并且很严重。有关中性粒细胞如何 在目前缺乏 HSCT 后，随着时间的推移，蜂群缺陷会得到解决。为了解决这一知识差距 为了评估新生物标志物的效用，我们将追求以下具体目标：1) 确定中性粒细胞 健康和 HSCT 患者中不同的蜂群参数。 2) 确定哪些细胞因子有助于恢复 HSCT 患者中性粒细胞的集群活动以及 3) 设计新的无标记成像技术 跟踪人类中性粒细胞对体内微观组织损伤的反应。如果成功的话，建议 研究可能通过改善对 HSCT 患者康复情况的监测对他们的生活产生重大影响 并通过确定加速中​​性粒细胞功能恢复和改善的潜在策略 它们对真菌感染的保护作用。