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; 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 肺移植可改善终末期肺部疾病患者的生存和生活质量。主要移植 功能障碍（PGD）和急性肺同种异体功能障碍（ALAD）分别是早期和中间事件 这威胁着移植的长期益处并增加了慢性肺同种异体移植的机会 功能障碍（外壳） - 肺移植受者长期死亡率的主要原因。努力 改善患者预后，部分原因是使用风险分层来指导肺部的临床决策 移植。具体而言，肺分配评分（LAS）根据 在被列出的一年内死亡以及移植后一年生存的可能性。估计 PGD​​和Alad的风险可能会带来更多分层的机会。但是，为了预测PGD 或Alad准确地说，接受者和供体风险因素与这些结果有很强的联系 被识别。大多数临床风险因素与PGD或ALAD没有足够的牢固关联来促进 预测结果的改善。在PGD或ALD的发病机理中具有机械作用的生物标志物 可能是这些结果的有力预测指标。值得注意的是，越来越多的证据表明 外泌体 - 直径为30-150nm的脂质结合细胞外蔬菜 - 从免疫和非免疫中解释 细胞 - 调节多种疾病中对抗原的免疫反应。我们的团队最近提出了一个 外泌体在先天和适应性免疫中的作用的概念框架预测发展 PGD​​，Alad和clad。我们最近证明了测量受体衍生的外泌体的可行性 在末期肺部疾病和初步数据的患者中，外泌体之间存在关联 表型和外壳。但是，是否有待确定接受者衍生的外泌体表型 与PGD或ALAD相关，移植后外泌体表型的变化以及如果是这样，则 这些变化是否增加了阿拉德的风险。为了解决这些知识差距，我们提出了三年 前瞻性队列研究对肺移植受者进行了一年的随访，其目的是：1） 确定接受者衍生的外泌体表型是否与PGD相关联，2）确定接受者是否衍生 外泌体表型与Alad相关，3）确定PGD是否改变了外泌体表型。 移植和/或阿拉德的风险。我们研究的最终目的是通过 对预测PGD和ALAD的生物标志物的了解越来越多。接受者之间有关联的证据 - 派生的外泌体表型和PGD和ALAD完成了开发风险分层的第一步 更好地告知移植受者选择和捐助者匹配的工具，并进一步指导免疫抑制 和其他移植后管理方案。预计这一投资也将增强我们的 对外泌体介导的免疫调节的了解，为外泌体在 PGD​​和ALAD的发病机理以及新的治疗靶标，用于未来的研究。