Lung transplant recipient exosome phenotypes and the risk of primary graft dysfunction and acute lung allograft dysfunction

肺移植受者外泌体表型以及原发性移植物功能障碍和急性肺同种异体移植物功能障碍的风险

• 批准号: 10426535
• 负责人: Farhood Farjah
• 金额: $ 44.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426535
• 关键词: Acute; Address; American; Antigens; Area; Biological Markers; Blood; Caliber; Cells; Chronic; Clinical; Clinical Research; Collection; Cytometry; Data; Data Collection; Development; Disease; Event; Exhibits; Eye; Fred Hutchinson Cancer Research Center; Functional disorder; Future; Goals; Immune; Immune response; Immunosuppression; Infrastructure; Investigation; Knowledge; Lead; Lipid Binding; Lung; Lung Transplantation; Lung diseases; Measurement; Measures; Mediating; Methodology; Michigan; Modification; National Heart, Lung, and Blood Institute; Natural Immunity; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Phenotype; Probability; Prognostic Marker; Prospective cohort study; Protocols documentation; Quality of life; Raman Spectrum Analysis; Reporting; Research; Research Design; Research Priority; Risk; Risk Estimate; Risk Factors; Role; Sampling; Specimen; Statistical Data Interpretation; Stratification; Therapeutic Intervention; Thoracic Surgical Procedures; Transplant Recipients; Transplantation; Transplantation Immunology; Universities; Validation; Washington; Wisconsin; adaptive immunity; base; biobank; cell type; clinical risk; cohort; exosome; extracellular vesicles; follow-up; graft dysfunction; high risk; immunoregulation; improved; innovation; insight; lung allograft; mortality; mortality risk; new therapeutic target; novel; novel therapeutic intervention; outcome prediction; post-transplant; predictive marker; predictive modeling; risk prediction; risk stratification; targeted treatment; tool; vesicular release

ABSTRACT Lung transplantation improves survival and quality-of-life for patients with end-stage lung disease. Primary graft dysfunction (PGD) and acute lung allograft dysfunction (ALAD) are early and intermediate events, respectively, that threaten the long-term benefits of transplantation and increase the chances of chronic lung allograft dysfunction (CLAD)—the primary cause of long-term mortality among lung transplant recipients. Efforts to improve patient outcomes have relied, in part, on the use of risk-stratification to guide clinical decisions in lung transplantation. Specifically, the Lung Allocation Score (LAS) ranks transplant candidates based on the risk of death within one year of being listed and the probability of survival one year after transplantation. The estimated risk of PGD and ALAD may present additional opportunities for stratification. However, in order to predict PGD or ALAD accurately, recipient and donor risk factors exhibiting a strong association with these outcomes must be identified. Most clinical risk factors do not have sufficiently strong associations with PGD or ALAD to facilitate improvements in prediction outcomes. Biomarkers with a mechanistic role in the pathogenesis of PGD or ALD are likely to be the strongest predictors of these outcomes. Notably, a growing body of evidence shows that exosomes—30-150nm diameter lipid bound extracellular vesicles—released from immune and non-immune cells—modulate the immune response to antigens in a variety of diseases. Our team recently proposed a conceptual framework for the role of exosomes in innate and adaptive immunity that predicts the development of PGD, ALAD, and CLAD. We recently demonstrated the feasibility of measuring recipient-derived exosomes in patients with end-stage lung diseases and preliminary data suggest an association between exosome phenotypes and CLAD. However, it remains to be determined whether recipient-derived exosome phenotypes are associated with PGD or ALAD, whether changes in exosome phenotype occur post-transplant and if so, whether these changes increase the risk of ALAD. To address these knowledge gaps, we propose a three-year prospective cohort study with one-year follow-up of lung transplant recipients with the following aims: 1) Determine if recipient-derived exosome phenotypes are associated with PGD, 2) Determine if recipient-derived exosome phenotypes are associated with ALAD, and 3) Determine if PGD alters exosome phenotype post- transplant and/or the risk of ALAD. The ultimate goal of our research is to improve patient outcomes by increasing knowledge of biomarkers that predict PGD and ALAD. Evidence of an association between recipient- derived exosome phenotypes and PGD and ALAD accomplishes the first step of developing a risk-stratification tool to better inform transplant recipient selection and donor matching, and to further guide immunosuppression and other post-transplant management protocols. This line of investigation is also expected to enhance our knowledge of exosome-mediated immunoregulation, providing novel insights into the role of exosomes in the pathogenesis of PGD and ALAD and novel therapeutic targets for future investigation.

抽象的 肺移植可提高终末期肺病患者的生存率和生活质量。 功能障碍（PGD）和急性肺同种异体移植功能障碍（ALAD）分别是早期和中期事件， 这威胁到移植的长期效益并增加慢性同种异体肺移植的机会 功能障碍（CLAD）——肺移植受者长期死亡的主要原因。 改善患者的治疗效果在一定程度上依赖于使用风险分层来指导肺部疾病的临床决策 具体来说，肺分配评分（LAS）根据移植候选者的风险进行排名。 上市后一年内的死亡和移植后一年内的生存概率。 然而，为了预测 PGD，PGD 和 ALAD 的风险可能会提供额外的分层机会。 或 ALAD 准确地说，受赠者和捐献者的风险因素必须与这些结果密切相关 大多数临床危险因素与 PGD 或 ALAD 之间的关联性不够强，无法促进诊断。 在 PGD 或 ALD 发病机制中具有机械作用的生物标志物的改善。 值得注意的是，越来越多的证据表明， 外泌体——直径 30-150nm 的脂质结合细胞外囊泡——从免疫和非免疫细胞中释放 细胞——调节多种疾病中抗原的免疫反应。 外泌体在先天性和适应性免疫中的作用的概念框架，可预测发展 我们最近证明了测量受体来源的外泌体的可行性。 在患有终末期肺病的患者中，初步数据表明外泌体之间存在关联 表型和 CLAD 然而，是否衍生外泌体表型仍有待确定。 与 PGD 或 ALAD 相关，外泌体表型的变化是否发生在移植后，如果是， 这些变化是否会增加 ALAD 的风险。为了解决这些知识差距，我们提出了为期三年的计划。 对肺移植受者进行一年随访的前瞻性队列研究，目的如下：1) 确定受体来源的外泌体表型是否与 PGD 相关，2) 确定受体来源的外泌体是否与 PGD 相关。 外泌体表型与 ALAD 相关，3) 确定 PGD 后是否改变外泌体表型 移植和/或 ALAD 的风险 我们研究的最终目标是通过以下方式改善患者的治疗结果。 增加对预测 PGD 和 ALAD 之间相关性的生物标志物的了解。 衍生的外泌体表型以及 PGD 和 ALAD 完成了制定风险分层的第一步 更好地为移植受者选择和供体匹配提供信息，并进一步指导免疫抑制的工具 和其他移植后管理协议也有望增强我们的研究。 外泌体介导的免疫调节的知识，为外泌体在免疫调节中的作用提供了新的见解 PGD​​ 和 ALAD 的发病机制以及未来研究的新治疗靶点。