Pay Your Dues Members Only Area
Central Surgical Association

49th Annual Meeting

Back to 2022 Abstracts


Identification of Circulating Exosome Subsets that Predict the Development of Chronic Allograft Dysfunction (CLAD) after Lung Transplantation in Patients with Cystic Fibrosis
Billanna Hwang, Erika Lease, James Bryers, *Michael Mulligan
Surgery, University of Washington, Seattle, Washington, United States

Lung transplantation is the only treatment option for patients with Cystic Fibrosis (CF) and end-stage lung disease. Despite advances in surgical techniques and post-transplant care, patient with CF who have undergone lung transplantation have a 45% survival rate, 10 years post-transplant. A major cause of morbidity and mortality remains to be the development of chronic lung allograft dysfunction (CLAD). Lung transplant immunology and correlations to clinical outcomes continues to be an area of research that has been difficult to understand. There are several variables including surgical and clinical complications that can affect immune responses post-transplant and identifying other potential surrogate markers that reflect those changes have been difficult. Extracellular vesicles or exosomes could potentially play a significant role in the lung transplant immunology including the development of primary graft dysfunction, allorecognition, acute rejection, and CLAD. In these studies, we focused on characterizing circulating exosomes in a discovery cohort of CF lung transplant recipients (LTRs) and correlating these profiles with the development of CLAD. Blood samples were collected from CF LTRs at various time points post-lung transplant (LTx). Exosomes were isolated from serum at 1-, 3-, 6-, and 12-months post-transplant and assessed for macrophage phenotypes (CD68, CD86, and CD163) and macrophage origin (alveolar, interstitial, and monocytes - CD169, CD206, PDL1, and CD14) using a novel flow cytometric method developed within our laboratory. Clinical data was extracted, and patients adjudicated and stratified for CLAD or no CLAD. Multivariable analysis was performed and potential associations with the development of CLAD. Results showed the CD68+CD86+ and CD68+CD163+ exosomes appeared to be prognostic indicators for the development of CLAD as early as 1-month post-transplant (p=.0243 and p=.0555, respectively; p<=.10 as significant). To identify whether circulating macrophage-derived exosomes originated from the lung, we examined the expression of markers that delineate alveolar, interstitial, or monocytic sources. Patient samples was assessed for expression of surface markers CD169, CD206, CD14, and PDL1 to identify the origin of exosomes. Co-expression of markers delineated alveolar macrophage (AM - CD169+PDL1+), interstitial macrophage (IM - CD206+CD169-), and monocytes (CD14+CD206+). AM-derived exosomes were markedly reduced in patients developing CLAD at 3 and 12 months (p=.0147 and <.00001, respectively) with a concurrent reduction in monocyte-derived exosomes at 12 months (p=.0193). Elevated levels of AM-derived exosomes were detected at 1-month post-transplant for both CLAD and no CLAD cohorts, while the no CLAD patients had consistent elevated levels up to 12 months post-transplant. Monocyte-derived exosomes were significantly decreased in CLAD patients, 12 months post-transplant (p=.0193). IM-derived exosomes appear to not be significant in any time point. These data suggest that there is an active role for macrophage-derived exosomes as key mediators in early host immune responses after lung transplantation. The discovery of these findings could be the missing link to understanding the development of CLAD amongst other immune-based post-transplant events. These profiles could be used to develop a novel prognostic platform for early determination of adverse clinical events providing an invaluable tool in treating patients.


Back to 2022 Abstracts