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）是治疗患者的基本程序， 血液恶性肿瘤也暂时增加了感染侵袭性真菌的风险。恢复 HSCT后中性粒细胞数量的增加通常被认为是恢复抗真菌治疗的关键指标。 的防御合作.然而，该指标是不精确的，并且迫切需要新的生物标志物来帮助识别 患者有风险。在缺乏新工具的情况下，侵袭性真菌感染的管理仍然显着 挑战性本研究的长期目标是设计新的工具并验证新的度量估计 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 群集功能，这是有效的抗真菌免疫反应的关键。集群不同于 吞噬作用，因为它涉及嗜中性粒细胞-中性粒细胞通信，有助于协调 多个细胞来阻止入侵真菌的生长。对中性粒细胞群集的关注是合理的， 初步结果显示，在HSCT患者中，即使中性粒细胞计数在术后4周恢复， 移植后，中性粒细胞群集缺陷仍然存在，并且是实质性的。关于中性粒细胞如何 在目前缺乏HSCT之后，群集缺陷随着时间的推移而解决。为了弥补这一知识差距， 评价新的生物标志物的效用，我们将追求以下具体目标：1）确定中性粒细胞 群集参数在健康和HSCT患者中不同。2)确定哪些细胞因子有助于恢复 HSCT患者中性粒细胞的群集活动; 3）设计新的无标记成像技术 跟踪人体中性粒细胞对体内微观组织损伤的反应。如果成功，建议 通过改善对HSCT患者恢复的监测，研究可能对HSCT患者的生活产生重大影响 并通过确定加速其中性粒细胞功能恢复的潜在策略， 它们对真菌感染的保护。