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

摘要 肺移植可改善终末期肺部疾病患者的存活率和生活质量。一期移植物 功能障碍(PGD)和急性同种异体肺移植功能障碍(ALAD)分别是早期和中期事件， 这威胁到移植的长期益处，增加了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。努力实现 改善患者预后在一定程度上依赖于使用风险分层来指导肺部的临床决策。 移植。具体地说，肺分配评分(LAS)根据移植对象的风险对移植对象进行排名 入选后一年内死亡及移植后一年存活概率。估计 PGD和ALAD的风险可能会带来更多的分层机会。然而，为了预测PGD 或ALAD准确地说，表明与这些结果有强烈关联的受者和捐赠者的风险因素必须 被指认出来。大多数临床风险因素与PGD或ALAD的相关性不够强， 改进了预测结果。生物标志物在PGD或ALD发病机制中的作用 很可能是这些结果的最强有力的预测因素。值得注意的是，越来越多的证据表明 胞外体-直径30-150 nm的脂类结合的胞外囊泡-从免疫和非免疫释放 细胞--在多种疾病中调节对抗原的免疫反应。我们的团队最近提出了一项 预测发育的外来体在先天免疫和获得性免疫中作用的概念框架 包括PGD、ALAD和CLAD。我们最近证明了测量受体来源的外切体的可行性。 在终末期肺部疾病患者中，初步数据表明外切体与 表型和穿着。然而，受体衍生的外切体表型是否存在还有待确定。 与PGD或ALAD相关，无论外切体表型是否在移植后发生变化，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，我们提议一项为期三年的 肺移植受者一年随访的前瞻性队列研究，目的如下：1) 确定受体来源的外切体表型是否与PGD相关，2)确定是否由受体来源 外显子表型与ALAD相关，3)决定PGD是否改变外显子后的表型。 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预后 增加预测PGD和ALAD的生物标志物的知识。收件人之间有关联的证据- 衍生的外切体表型和PGD和ALAD完成了发展风险分层的第一步 更好地通知移植受者选择和捐赠者匹配，并进一步指导免疫抑制的工具 和其他移植后管理方案。这一调查路线预计也将加强我们的 了解外切体介导的免疫调节，为了解外切体在免疫中的作用提供了新的见解。 PGD和ALAD的发病机制及未来研究的新靶点。

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.