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.

摘要 肺移植可提高终末期肺病患者的生存率和生活质量原发性移植物 肺移植物功能障碍（PGD）和急性肺移植物功能障碍（ALAD）分别是早期和中期事件， 这会威胁到移植的长期利益，并增加慢性肺移植的机会。 肺功能障碍（CLAD）-肺移植受者长期死亡的主要原因。努力 改善患者预后部分依赖于使用风险分层来指导肺部疾病的临床决策， 移植具体而言，肺分配评分（LAS）根据以下风险对移植候选人进行排名： 登记后一年内的死亡率和移植后一年的存活率。估计 PGD和ALAD的风险可能提供额外的分层机会。然而，为了预测PGD 或ALAD准确，受体和供体风险因素表现出与这些结果的强相关性，必须 被识别。大多数临床风险因素与PGD或ALAD的关联性不足以促进 改善预测结果。在PGD或ALD发病机制中具有机制作用的生物标志物 很可能是这些结果的最强预测者。值得注意的是，越来越多的证据表明， 外泌体-直径为30- 150 nm的脂质结合的细胞外囊泡-从免疫和非免疫释放 细胞调节多种疾病中对抗原的免疫应答。我们的团队最近提出了一个 外泌体在先天性和适应性免疫中作用的概念框架，可预测 PGD、ALAD和CLAD。我们最近证明了测量肿瘤来源的外泌体的可行性， 在终末期肺病患者中，初步数据表明外泌体 表型和CLAD。然而，还有待确定的是， 是否与PGD或ALAD相关，是否在移植后发生外泌体表型的变化，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，我们提出了一个为期三年的 一项前瞻性队列研究，对肺移植受者进行为期一年的随访，目的如下：1） 2）确定是否存在与PGD相关的细胞来源的外泌体表型， 外泌体表型与ALAD相关，以及3）确定PGD是否改变了ALAD后的外泌体表型。 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效果： 增加预测PGD和ALAD的生物标志物的知识。有证据表明收件人- 衍生的外泌体表型和PGD和ALAD完成了风险分层的第一步 更好地为移植受体选择和供体匹配提供信息，并进一步指导免疫抑制的工具 以及其他移植后管理方案。这一调查路线也有望提高我们的 外泌体介导的免疫调节的知识，提供了新的见解外泌体的作用， PGD和ALAD的发病机制以及未来研究的新治疗靶点。