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

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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.