Monal Sharma1, Muthukumar Gunasekaran1, Ranjithkumar Ravichandran1, Cynthia E Fisher2, Ajit P Limaye2, Chengcheng Hu3, John McDyer4, Vaidehi Kaza5, Ankit Bharat6, Sofya Tokman1, Ashraf Omar1, Ashwini Arjuna1, Rajat Walia1, Ross M Bremner1, Michael A Smith1, Ramsey R Hachem7, Thalachallour Mohanakumar8. 1. Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona. 2. Deparment of Medicine, University of Washington, Seattle, Washington. 3. Department of Epidemiology and Biostatistics, University of Arizona, Phoenix, Arizona. 4. Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. 5. Internal Medicine-Pulmonary Disease, University of Texas Southwestern, Dallas, Texas. 6. Department of Surgery-Thoracic, Northwestern University, Chicago, Illinois. 7. Department of Internal Medicine, Washington University Medical School, St Louis, Missouri. 8. Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona. Electronic address: tm.kumar@dignityhealth.org.
Abstract
BACKGROUND: Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS. METHODS: Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software. RESULTS: Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs-containing exosomes at 6 and 12 months before BOS. CONCLUSIONS: Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.
BACKGROUND: Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS. METHODS: Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software. RESULTS: Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs-containing exosomes at 6 and 12 months before BOS. CONCLUSIONS: Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.
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