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Xu W, Boer K, Hesselink DA, Baan CC. Extracellular Vesicles and Immune Activation in Solid Organ Transplantation: The Impact of Immunosuppression. BioDrugs 2025; 39:445-459. [PMID: 40140222 PMCID: PMC12031870 DOI: 10.1007/s40259-025-00713-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 03/28/2025]
Abstract
Recent advances in extracellular vesicle (EV) research in organ transplantation have highlighted the crucial role of donor-derived EVs in triggering alloimmune responses, ultimately contributing to transplant rejection. Following transplantation, EVs carrying donor major histocompatibility complex (MHC) molecules activate recipient antigen-presenting cells (APCs), initiating both alloreactive and regulatory T-cell responses. While immunosuppressive drugs are essential for preventing rejection, they may also influence the biogenesis and release of EVs from donor cells. This review examines the impact of maintenance immunosuppressive therapy on EV biogenesis and release post-transplantation. In addition, EV release and uptake may be influenced by specific factors such as the patient's end-stage organ disease and the transplant procedure itself. In-vitro studies using primary human parenchymal and immune cells-integrated with cutting-edge multi-omics techniques, including genomics, proteomics, lipidomics, and single-EV analysis-will offer deeper insights into EV biology and the mechanisms by which immunosuppressive agents regulate EV-initiated immune processes. A detailed understanding of how organ failure, the transplantation procedure and immunosuppressive drugs affect the biology of EVs may uncover new roles for EVs in immune activation and regulation in patients, ultimately leading to improved immunosuppressive strategies and better transplant outcomes.
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Affiliation(s)
- Weicheng Xu
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands.
| | - Karin Boer
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
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Delshad M, Sanaei MJ, Mohammadi MH, Sadeghi A, Bashash D. Exosomal Biomarkers: A Comprehensive Overview of Diagnostic and Prognostic Applications in Malignant and Non-Malignant Disorders. Biomolecules 2025; 15:587. [PMID: 40305328 PMCID: PMC12024574 DOI: 10.3390/biom15040587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025] Open
Abstract
Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to the high cost and invasive nature of current diagnostic procedures. Exosomes have a clear advantage in the diagnosis of diseases because they include certain signals that are indicative of the genetic and proteomic profile of the ailment. This feature gives them the potential to be useful liquid biopsies for real-time, noninvasive monitoring, enabling early cancer identification for the creation of individualized treatment plans. According to our analysis, the trend toward utilizing exosomes as diagnostic and prognostic tools has raised since 2012. In this regard, the proportion of malignant indications is higher compared with non-malignant ones. To be precise, exosomes have been used the most in gastrointestinal, thoracic, and urogenital cancers, along with cardiovascular, diabetic, breathing, infectious, and brain disorders. To the best of our knowledge, this is the first research to examine all registered clinical trials that look at exosomes as a diagnostic and prognostic biomarker.
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Affiliation(s)
- Mahda Delshad
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
- Department of Laboratory Sciences, School of Allied Medical Sciences, Zanjan University of Medical Sciences, Zanjan 1411718541, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran;
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
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Brugière O, Dreyfuss D, Guilet R, Rong S, Hirschi S, Renaud-Picard B, Reynaud-Gaubert M, Coiffard B, Bunel V, Messika J, Demant X, Le Pavec J, Dauriat G, Saint Raymond C, Falque L, Mornex JF, Tissot A, Lair D, Le Borgne Krams A, Bousseau V, Magnan A, Picard C, Roux A, Glorion M, Carmagnat M, Gazeau F, Aubertin K, Carosella E, Vallée A, Landais C, Rouas-Freiss N, LeMaoult J. Circulating Vesicular-bound HLA-G as Noninvasive Predictive Biomarker of CLAD After Lung Transplantation. Transplantation 2025; 109:736-745. [PMID: 39294868 DOI: 10.1097/tp.0000000000005175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
BACKGROUND Circulating extracellular vesicles (EVs) have shown promising results as noninvasive biomarkers for predicting disease outcomes in solid organ transplantation. Because in situ graft cell expression of the tolerogenic molecule HLA-G is associated with acceptance after lung transplantation (LTx), we hypothesized that plasma EV-bound HLA-G (HLA-G EV ) levels could predict chronic lung allograft dysfunction (CLAD) development. METHODS We analyzed 78 LTx recipients from the Cohort-for-Lung-Transplantation cohort, all in a stable (STA) state within the first year post-LTx. At 3 y, 41 patients remained STA, and 37 had CLAD (bronchiolitis obliterans syndrome, BOS, [n = 32] or restrictive allograft syndrome [n = 5]). HLA-G EV plasma levels were measured at month 6 (M6) and M12 in 78 patients. CLAD occurrence and graft failure at 3 y post-LTx were assessed according to early HLA-G EV plasma levels. RESULTS In patients with subsequent BOS, (1) HLA-G EV levels at M12 were significantly lower than those in STA patients ( P = 0.013) and (2) also significantly lower than their previous levels at M6 ( P = 0.04).A lower incidence of CLAD and BOS and higher graft survival at 3 y were observed in patients with high HLA-G EV plasma levels at M12 (high versus low HLA-G EVs patients [cutoff 21.3 ng/mL]: freedom from CLAD, P = 0.002; freedom from BOS, P < 0.001; and graft survival, P = 0.04, [log-rank]). Furthermore, in multivariate analyses, low HLA-G EV levels at M12 were independently associated with a subsequent risk of CLAD, BOS, and graft failure at 3 y ( P = 0.015, P = 0.036, and P = 0.026, respectively [Cox models]). CONCLUSIONS This exploratory study suggests the potential of EV-bound HLA-G plasma levels as a liquid biopsy in predicting CLAD/BOS onset and subsequent graft failure.
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Affiliation(s)
- Olivier Brugière
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
| | - Dora Dreyfuss
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
| | - Ronan Guilet
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
| | - Sophie Rong
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
| | - Sandrine Hirschi
- Department of Pneumology, Strasbourg Lung Transplant Program, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR 1260, Regenerative Nanomedicine, University of Strasbourg, Strasbourg, France
| | - Benjamin Renaud-Picard
- Department of Pneumology, Strasbourg Lung Transplant Program, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR 1260, Regenerative Nanomedicine, University of Strasbourg, Strasbourg, France
| | | | - Benjamin Coiffard
- Service de Pneumologie et Transplantation Pulmonaire, CHU de Marseille, Marseille, France
| | - Vincent Bunel
- APHP.Nord-Université de Paris, Hôpital Bichat-Claude Bernard, Service de Pneumologie B et Transplantation Pulmonaire, Paris, France
| | - Jonathan Messika
- APHP.Nord-Université de Paris, Hôpital Bichat-Claude Bernard, Service de Pneumologie B et Transplantation Pulmonaire, Paris, France
| | - Xavier Demant
- Service de Pneumologie et Transplantation Pulmonaire, CHU de Bordeaux, Bordeaux, France
| | - Jérôme Le Pavec
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France
| | - Gaelle Dauriat
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France
| | - Christel Saint Raymond
- Service Hospitalier Universitaire de Pneumologie et Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Échirolles, France
| | - Loic Falque
- Service Hospitalier Universitaire de Pneumologie et Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Échirolles, France
| | - Jean-Francois Mornex
- Université Claude Bernard Lyon1, INRAE, IVPC, Lyon, France
- Hospices Civils de Lyon, Inserm CIC1407, Bron, France
| | - Adrien Tissot
- Nantes Université, CHU Nantes, INSERM, Service de Pneumologie, l'institut du thorax, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - David Lair
- Nantes Université, CHU Nantes, INSERM, Service de Pneumologie, l'institut du thorax, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | | | - Veronique Bousseau
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital HEGP, Paris, France
| | - Antoine Magnan
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | - Clément Picard
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | - Antoine Roux
- Service de Pneumologie et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | | | | | - Florence Gazeau
- Université Paris Cité, MSC et intégrateur IVETh, CNRS UMR7057, Paris, France
| | - Kelly Aubertin
- Université Paris Cité, MSC et intégrateur IVETh, CNRS UMR7057, Paris, France
| | - Edgardo Carosella
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
| | - Alexandre Vallée
- Service d'épidémiologie et santé publique, Hôpital Foch, Suresnes, France
| | - Cecile Landais
- Departement de biostatistiques, DRCI Hôpital Foch, Suresnes, France
| | - Nathalie Rouas-Freiss
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
| | - Joel LeMaoult
- CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- U976 HIPI, IRSL, Université Paris Cité, Paris, France
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Bery AI, Belousova N, Hachem RR, Roux A, Kreisel D. Chronic Lung Allograft Dysfunction: Clinical Manifestations and Immunologic Mechanisms. Transplantation 2025; 109:454-466. [PMID: 39104003 PMCID: PMC11799353 DOI: 10.1097/tp.0000000000005162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2024]
Abstract
The term "chronic lung allograft dysfunction" has emerged to describe the clinical syndrome of progressive, largely irreversible dysfunction of pulmonary allografts. This umbrella term comprises 2 major clinical phenotypes: bronchiolitis obliterans syndrome and restrictive allograft syndrome. Here, we discuss the clinical manifestations, diagnostic challenges, and potential therapeutic avenues to address this major barrier to improved long-term outcomes. In addition, we review the immunologic mechanisms thought to propagate each phenotype of chronic lung allograft dysfunction, discuss the various models used to study this process, describe potential therapeutic targets, and identify key unknowns that must be evaluated by future research strategies.
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Affiliation(s)
- Amit I Bery
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Natalia Belousova
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
| | - Ramsey R Hachem
- Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Antoine Roux
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
- Paris Transplant Group, INSERM U 970s, Paris, France
| | - Daniel Kreisel
- Departments of Surgery, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
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Rahman M, Scozzi D, Eguchi N, Klein R, Sankpal NV, Sureshbabu A, Fleming T, Hachem R, Smith M, Bremner R, Mohanakumar T. Downregulation of Tumor Suppressor Gene LKB1 During Severe Primary Graft Dysfunction After Human Lung Transplantation: Implication for the Development of Chronic Lung Allograft Dysfunction. Transplantation 2025; 109:476-483. [PMID: 39228019 DOI: 10.1097/tp.0000000000005172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
BACKGROUND Severe primary graft dysfunction (PGD) after lung transplantation (LTx) is a significant risk factor for the development of bronchiolitis obliterans syndrome (BOS). Recent data from our group demonstrated that small extracellular vesicles (sEVs) isolated from the plasma of LTx recipients with BOS have reduced levels of tumor suppressor gene liver kinase B1 ( LKB1 ) and promote epithelial-to-mesenchymal transition (EMT) and fibrosis. Here, we hypothesized that early inflammatory responses associated with severe PGD (PGD2/3) can downregulate LKB1 levels in sEVs, predisposing to the development of chronic lung allograft dysfunction (CLAD). METHODS sEVs were isolated from the plasma of human participants by Exosome Isolation Kit followed by 0.20-µm filtration and characterized by NanoSight and immunoblotting analysis. Lung self-antigens (K alpha 1 tubulin, Collagen V), LKB1 , nuclear factor kappa B, and EMT markers in sEVs were compared by densitometry analysis between PGD2/3 and no-PGD participants. Neutrophil-derived factors and hypoxia/reperfusion effects on LKB1 levels and EMT were analyzed in vitro using quantitative real-time polymerase chain reaction and Western blotting. RESULTS LKB1 was significantly downregulated in PGD2/3 sEVs compared with no-PGD sEVs. Within PGD2/3 participants, lower post-LTx LKB1 was associated with CLAD development. Hypoxia/reperfusion downregulates LKB1 and is associated with markers of EMT in vitro. Finally, lower LKB1 levels in PGD2/3 are associated with increased markers of EMT. CONCLUSIONS Our results suggest that in post-LTx recipients with PGD2/3, downregulation of LKB1 protein levels in sEVs is associated with increased EMT markers and may result in the development of CLAD. Our results also suggest that ischemia/reperfusion injury during LTx may promote CLAD through the early downregulation of LKB1 .
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Affiliation(s)
- Mohammad Rahman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Davide Scozzi
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Natsuki Eguchi
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Rachel Klein
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Narendra V Sankpal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Angara Sureshbabu
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Ramsey Hachem
- Washington University School of Medicine, St. Louis, MO
| | - Michael Smith
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | - Ross Bremner
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
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Cruz CG, Sodawalla HM, Mohanakumar T, Bansal S. Extracellular Vesicles as Biomarkers in Infectious Diseases. BIOLOGY 2025; 14:182. [PMID: 40001950 PMCID: PMC11851951 DOI: 10.3390/biology14020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 02/07/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025]
Abstract
Extracellular vesicles (EVs) are nanosized vesicles that are secreted by all cells into the extracellular space. EVs are involved in cell-to-cell communication and can be found in different bodily fluids (bronchoalveolar lavage fluid, sputum, and urine), tissues, and in circulation; the composition of EVs reflects the physiological condition of the releasing cell. The ability to use EVs from bodily fluids for minimally invasive detection to monitor diseases makes them an attractive target. EVs carry a snapshot of the releasing cell's internal state, and they can serve as powerful biomarkers for diagnosing diseases. EVs also play a role in the body's immune and pathogen detection responses. Pathogens, such as bacteria and viruses, can exploit EVs to enhance their survival and spread and to evade detection by the immune system. Changes in the number or contents of EVs can signal the presence of an infection, offering a potential avenue for developing new diagnostic methods for infectious diseases. Ongoing research in this area aims to address current challenges and the potential of EVs as biomarkers in diagnosing a range of diseases, including infections and infectious diseases. There is limited literature on the development of EVs as diagnostic biomarkers for infectious diseases using existing molecular biology approaches. We aim to address this gap by reviewing recent EV-related investigations in infectious disease studies.
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Affiliation(s)
- Cinthia Gonzalez Cruz
- Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA;
| | - Husain M. Sodawalla
- Department of Mechanical Engineering, Northern Arizona University, Flagstaff, AZ 86011, USA;
| | | | - Sandhya Bansal
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA;
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Ravichandran R, Rahman M, Bansal S, Scozzi D, Fleming T, Ratti G, Arjuna A, Weigt S, Kaza V, Smith M, Bremner RM, Mohanakumar T. Reduced levels of liver kinase B1 in small extracellular vesicles as a predictor for chronic lung allograft dysfunction in cystic fibrosis lung transplant recipients. Hum Immunol 2025; 86:111187. [PMID: 39612537 DOI: 10.1016/j.humimm.2024.111187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/09/2024] [Accepted: 11/12/2024] [Indexed: 12/01/2024]
Abstract
Small extracellular vesicles (sEVs) isolated from plasma of lung transplant recipients (LTRs) with chronic lung allograft dysfunction (CLAD) contain increased levels of lung associated self-antigens, Kα1 tubulin and collagen V, and decreased expression of the tumor suppressor liver kinase B1 (LKB1). In this study, sEVs were isolated from plasma collected from LTRs with or without cystic fibrosis (CF) from multiple centers at the onset of CLAD and 6 and 12 months before clinical diagnosis of CLAD (n = 32) as well as from time-matched stable controls (n = 25). sEVs were analyzed for Kα1 tubulin, collagen V, and LKB1 by western blot. Exoview R200, a functionalized microarray chip was employed to characterize the LKB1 in sEVs. EVs from non-CF LTRs had higher levels of lung self-antigens (p < 0.05) and lower levels of LKB1 (p = 0.024) 12 months before CLAD diagnosis than those from time-matched stable LTRs; however, in CF LTRs, only LKB1 levels were lower (p = 0.0005) 6 months before diagnosis. Further characterization of sEVs 6 months before CLAD in CF LTRs also demonstrated significantly lower numbers of LKB1 and LKB1/CD9 + sEV particles. Reduced LKB1 in circulating sEVs offers a potential biomarker for the risk of CLAD in LTRs with CF.
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Affiliation(s)
- Ranjithkumar Ravichandran
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Mohammad Rahman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Davide Scozzi
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Gregory Ratti
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, United States
| | - Ashwini Arjuna
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Samuel Weigt
- Division of Pulmonary, Critical Care, Allergy and Immunology, University of California Los Angeles, Los Angeles, CA 90095, United States
| | - Vaidehi Kaza
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, United States
| | - Michael Smith
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Ross M Bremner
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States
| | - Thalachallour Mohanakumar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W Thomas Road, Suite 105, Phoenix, AZ 85013, United States.
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Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
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Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
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Benichou G, Lancia HH. Intercellular transfer of MHC molecules in T cell alloimmunity and allotransplantation. Biomed J 2024; 47:100749. [PMID: 38797478 PMCID: PMC11414654 DOI: 10.1016/j.bj.2024.100749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 05/15/2024] [Accepted: 05/24/2024] [Indexed: 05/29/2024] Open
Abstract
After transplantation of allogeneic tissues and organs, recognition by recipient T cells of donor MHC molecules initiates the pro-inflammatory adaptive immune response leading to allograft rejection. T cell allorecognition has long been known to be mediated via two distinct pathways: the direct pathway in which T cells recognize intact allogeneic MHC molecules displayed on donor cells and the indirect pathway whereby T cells recognize donor MHC peptides processed and presented by recipient antigen-presenting cells (APCs). It is believed that direct allorecognition is the driving force behind early acute allograft rejection while indirect allorecognition is involved in chronic allograft rejection, a progressive condition characterized by graft vasculopathy and tissue fibrosis. Recently, we and others have reported that after transplantation of allogeneic skin and organs, donor MHC molecules are transferred from donor cells to the host's APCs via trogocytosis or extracellular vesicles. Recipient APCs having captured donor MHC molecules can either present them to T cells in their intact form on their surface (semi-direct pathway) or the form of peptides bound to self-MHC molecules (indirect pathway). The present article provides an overview of recent studies evaluating the role of intercellular exchange of MHC molecules in T cell alloimmunity and its contribution to allograft rejection and tolerance.
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Affiliation(s)
- Gilles Benichou
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, MA, USA.
| | - Hyshem H Lancia
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, MA, USA
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Ye D, Liu Q, Zhang C, Dai E, Fan J, Wu L. Relationship between immune cells and the development of chronic lung allograft dysfunction. Int Immunopharmacol 2024; 137:112381. [PMID: 38865754 DOI: 10.1016/j.intimp.2024.112381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024]
Abstract
A major cause of death for lung transplant recipients (LTRs) is the advent of chronic lung allograft dysfunction (CLAD), which has long plagued the long-term post-transplant prognosis and quality of survival of transplant patients. The intricacy of its pathophysiology and the irreversibility of its illness process present major obstacles to the clinical availability of medications. Immunotherapeutic medications are available, but they only aim to slow down the course of CLAD rather than having any therapeutic impact on the disease's development. For this reason, understanding the pathophysiology of CLAD is essential for both disease prevention and proven treatment. The immunological response in particular, in relation to chronic lung allograft dysfunction, has received a great deal of interest recently. Innate immune cells like natural killer cells, eosinophils, neutrophils, and mononuclear macrophages, as well as adaptive immunity cells like T and B cells, play crucial roles in this process through the release of chemokines and cytokines. The present review delves into changes and processes within the immune microenvironment, with a particular focus on the quantity, subtype, and characteristics of effector immune cells in the peripheral and transplanted lungs after lung transplantation. We incorporate and solidify the documented role of immune cells in the occurrence and development of CLAD with the advancements in recent years.
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Affiliation(s)
- Defeng Ye
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiongliang Liu
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Zhang
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Enci Dai
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiang Fan
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Liang Wu
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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11
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Napoli C, Benincasa G, Fiorelli A, Strozziero MG, Costa D, Russo F, Grimaldi V, Hoetzenecker K. Lung transplantation: Current insights and outcomes. Transpl Immunol 2024; 85:102073. [PMID: 38889844 DOI: 10.1016/j.trim.2024.102073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 06/10/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
Until now, the ability to predict or retard immune-mediated rejection events after lung transplantation is still limited due to the lack of specific biomarkers. The pressing need remains to early diagnose or predict the onset of chronic lung allograft dysfunction (CLAD) and its differential phenotypes that is the leading cause of death. Omics technologies (mainly genomics, epigenomics, and transcriptomics) combined with advanced bioinformatic platforms are clarifying the key immune-related molecular routes that trigger early and late events of lung allograft rejection supporting the biomarker discovery. The most promising biomarkers came from genomics. Both unregistered and NIH-registered clinical trials demonstrated that the increased percentage of donor-derived cell-free DNA in both plasma and bronchoalveolar lavage fluid showed a good diagnostic performance for clinically silent acute rejection events and CLAD differential phenotypes. A further success arose from transcriptomics that led to development of Molecular Microscope® Diagnostic System (MMDx) to interpret the relationship between molecular signatures of lung biopsies and rejection events. Other immune-related biomarkers of rejection events may be exosomes, telomer length, DNA methylation, and histone-mediated neutrophil extracellular traps (NETs) but none of them entered in registered clinical trials. Here, we discuss novel and existing technologies for revealing new immune-mediated mechanisms underlying acute and chronic rejection events, with a particular focus on emerging biomarkers for improving precision medicine of lung transplantation field.
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Affiliation(s)
- Claudio Napoli
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; U.O.C. Division of Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, Clinical Department of Internal Medicine and Specialistics, University of Campania "L. Vanvitelli,", Naples, Italy
| | - Giuditta Benincasa
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
| | - Alfonso Fiorelli
- Thoracic Surgery Unit, Department of Translation Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | | | - Dario Costa
- U.O.C. Division of Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, Clinical Department of Internal Medicine and Specialistics, University of Campania "L. Vanvitelli,", Naples, Italy
| | | | - Vincenzo Grimaldi
- U.O.C. Division of Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, Clinical Department of Internal Medicine and Specialistics, University of Campania "L. Vanvitelli,", Naples, Italy
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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12
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Jennings H, McMorrow S, Chlebeck P, Heise G, Levitsky M, Verhoven B, Kink JA, Weinstein K, Hong S, Al‐Adra DP. Normothermic liver perfusion derived extracellular vesicles have concentration-dependent immunoregulatory properties. J Extracell Vesicles 2024; 13:e12485. [PMID: 39051751 PMCID: PMC11270586 DOI: 10.1002/jev2.12485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 06/27/2024] [Indexed: 07/27/2024] Open
Abstract
Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross-decoration'. In contrast, donor liver-derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant-relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti-inflammatory miRNA species. In terms of function, liver-derived EVs were able to cross-decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration-dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF-α, IL-10 and IFN-γ. In conclusion, we determined physiologically produced liver-derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation.
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Affiliation(s)
- Heather Jennings
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Stacey McMorrow
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Peter Chlebeck
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Grace Heise
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Mia Levitsky
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Bret Verhoven
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - John A. Kink
- Department of MedicineUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Kristin Weinstein
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
| | - Seungpyo Hong
- Pharmaceutical Sciences Division, School of PharmacyUniversity of Wisconsin‐MadisonMadisonWisconsinUSA
| | - David P. Al‐Adra
- Department of Surgery, Division of TransplantationUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA
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13
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Pan W, Li S, Li K, Zhou P. Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Potential in Organ Transplantation. Stem Cells Int 2024; 2024:2043550. [PMID: 38708382 PMCID: PMC11068458 DOI: 10.1155/2024/2043550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 05/07/2024] Open
Abstract
At present, organ transplantation remains the most appropriate therapy for patients with end-stage organ failure. However, the field of organ transplantation is still facing many challenges, including the shortage of organ donors, graft function damage caused by organ metastasis, and antibody-mediated immune rejection. It is therefore urgently necessary to find new and effective treatment. Stem cell therapy has been regarded as a "regenerative medicine technology." Mesenchymal stem cells (MSCs), as the most common source of cells for stem cell therapy, play an important role in regulating innate and adaptive immune responses and have been widely used in clinical trials for the treatment of autoimmune and inflammatory diseases. Increasing evidence has shown that MSCs mainly rely on paracrine pathways to exert immunomodulatory functions. In addition, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are the main components of paracrine substances of MSCs. Herein, an overview of the application of the function of MSCs and MSC-EVs in organ transplantation will focus on the progress reported in recent experimental and clinical findings and explore their uses for graft preconditioning and recipient immune tolerance regulation. Additionally, the limitations on the use of MSC and MSC-EVs are also discussed, covering the isolation of exosomes and preservation techniques. Finally, the opportunities and challenges for translating MSCs and MSC-EVs into clinical practice of organ transplantation are also evaluated.
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Affiliation(s)
- Wennuo Pan
- Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Shaohan Li
- Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Kunsheng Li
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Pengyu Zhou
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
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14
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Fernando JJ, Biswas R, Biswas L. Non-invasive molecular biomarkers for monitoring solid organ transplantation: A comprehensive overview. Int J Immunogenet 2024; 51:47-62. [PMID: 38200592 DOI: 10.1111/iji.12654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024]
Abstract
Solid organ transplantation is a life-saving intervention for individuals with end-stage organ failure. Despite the effectiveness of immunosuppressive therapy, the risk of graft rejection persists in all viable transplants between individuals. The risk of rejection may vary depending on the degree of compatibility between the donor and recipient for both human leucocyte antigen (HLA) and non-HLA gene-encoded products. Monitoring the status of the allograft is a critical aspect of post-transplant management, with invasive biopsies being the standard of care for detecting rejection. Non-invasive biomarkers are increasingly being recognized as valuable tools for aiding in the detection of graft rejection, monitoring graft status and evaluating the efficacy of immunosuppressive therapy. Here, we focus on the importance of molecular biomarkers in solid organ transplantation and their potential role in clinical practice. Conventional molecular biomarkers used in transplantation include HLA typing, detection of anti-HLA antibodies, killer cell immunoglobulin-like receptor genotypes, and anti-MHC class 1-related chain A antibodies, which are important for assessing the compatibility of the donor and recipient. Emerging molecular biomarkers include the detection of donor-derived cell-free DNA, microRNAs (regulation of gene expression), exosomes (small vesicles secreted by cells), and kidney solid organ response test, in the recipient's blood for early signs of rejection. This review highlights the strengths and limitations of these molecular biomarkers and their potential role in improving transplant outcomes.
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Affiliation(s)
- Jeffy J Fernando
- Amrita School of Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Raja Biswas
- Amrita School of Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Lalitha Biswas
- Amrita School of Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
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15
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Yadav R, Singh AV, Kushwaha S, Chauhan DS. Emerging role of exosomes as a liquid biopsy tool for diagnosis, prognosis & monitoring treatment response of communicable & non-communicable diseases. Indian J Med Res 2024; 159:163-180. [PMID: 38577857 PMCID: PMC11050750 DOI: 10.4103/ijmr.ijmr_2344_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Indexed: 04/06/2024] Open
Abstract
ABSTRACT From an initial thought of being used as a cellular garbage bin to a promising target for liquid biopsies, the role of exosomes has drastically evolved in just a few years of their discovery in 1983. Exosomes are naturally secreted nano-sized vesicles, abundant in all types of body fluids and can be isolated intact even from the stored biological samples. Being stable carriers of genetic material (cellular DNA, mRNA and miRNA) and having specific cargo (signature content of originating cells), exosomes play a crucial role in pathogenesis and have been identified as a novel source of biomarkers in a variety of disease conditions. Recently exosomes have emerged as a promising 'liquid biopsy tool'and have shown great potential in the field of non-invasive disease diagnostics, prognostics and treatment response monitoring in both communicable as well as non-communicable diseases. However, there are certain limitations to overcome which restrict the use of exosome-based liquid biopsy as a gold standard testing procedure in routine clinical practices. The present review summarizes the current knowledge on the role of exosomes as the liquid biopsy tool in diagnosis, prognosis and treatment response monitoring in communicable and non-communicable diseases and highlights the major limitations, technical advancements and future prospects of the utilization of exosome-based liquid biopsy in clinical interventions.
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Affiliation(s)
- Rajbala Yadav
- Department of Microbiology & Molecular Biology, ICMR-National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Agra, Uttar Pradesh, India
| | - Ajay Vir Singh
- Department of Microbiology & Molecular Biology, ICMR-National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Agra, Uttar Pradesh, India
| | - Shweta Kushwaha
- Department of Microbiology & Molecular Biology, ICMR-National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Agra, Uttar Pradesh, India
| | - Devendra Singh Chauhan
- Department of Microbiology & Molecular Biology, ICMR-National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Agra, Uttar Pradesh, India
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16
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Bansal S, Rahman M, Ravichandran R, Canez J, Fleming T, Mohanakumar T. Extracellular Vesicles in Transplantation: Friend or Foe. Transplantation 2024; 108:374-385. [PMID: 37482627 DOI: 10.1097/tp.0000000000004693] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
The long-term function of transplanted organs, even under immunosuppression, is hindered by rejection, especially chronic rejection. Chronic rejection occurs more frequently after lung transplantation, termed chronic lung allograft dysfunction (CLAD), than after transplantation of other solid organs. Pulmonary infection is a known risk factor for CLAD, as transplanted lungs are constantly exposed to the external environment; however, the mechanisms by which respiratory infections lead to CLAD are poorly understood. The role of extracellular vesicles (EVs) in transplantation remains largely unknown. Current evidence suggests that EVs released from transplanted organs can serve as friend and foe. EVs carry not only major histocompatibility complex antigens but also tissue-restricted self-antigens and various transcription factors, costimulatory molecules, and microRNAs capable of regulating alloimmune responses. EVs play an important role in antigen presentation by direct, indirect, and semidirect pathways in which CD8 and CD4 cells can be activated. During viral infections, exosomes (small EVs <200 nm in diameter) can express viral antigens and regulate immune responses. Circulating exosomes may also be a viable biomarker for other diseases and rejection after organ transplantation. Bioengineering the surface of exosomes has been proposed as a tool for targeted delivery of drugs and personalized medicine. This review focuses on recent studies demonstrating the role of EVs with a focus on exosomes and their dual role (immune activation or tolerance induction) after organ transplantation, more specifically, lung transplantation.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
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17
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Pradère P, Zajacova A, Bos S, Le Pavec J, Fisher A. Molecular monitoring of lung allograft health: is it ready for routine clinical use? Eur Respir Rev 2023; 32:230125. [PMID: 37993125 PMCID: PMC10663940 DOI: 10.1183/16000617.0125-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/16/2023] [Indexed: 11/24/2023] Open
Abstract
Maintenance of long-term lung allograft health in lung transplant recipients (LTRs) requires a fine balancing act between providing sufficient immunosuppression to reduce the risk of rejection whilst at the same time not over-immunosuppressing individuals and exposing them to the myriad of immunosuppressant drug side-effects that can cause morbidity and mortality. At present, lung transplant physicians only have limited and rather blunt tools available to assist them with this task. Although therapeutic drug monitoring provides clinically useful information about single time point and longitudinal exposure of LTRs to immunosuppressants, it lacks precision in determining the functional level of immunosuppression that an individual is experiencing. There is a significant gap in our ability to monitor lung allograft health and therefore tailor optimal personalised immunosuppression regimens. Molecular diagnostics performed on blood, bronchoalveolar lavage or lung tissue that can detect early signs of subclinical allograft injury, differentiate rejection from infection or distinguish cellular from humoral rejection could offer clinicians powerful tools in protecting lung allograft health. In this review, we look at the current evidence behind molecular monitoring in lung transplantation and ask if it is ready for routine clinical use. Although donor-derived cell-free DNA and tissue transcriptomics appear to be the techniques with the most immediate clinical potential, more robust data are required on their performance and additional clinical value beyond standard of care.
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Affiliation(s)
- Pauline Pradère
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
- Department of Respiratory Diseases, Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Paris, France
| | - Andrea Zajacova
- Prague Lung Transplant Program, Department of Pneumology, Motol University Hospital and 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Saskia Bos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
- Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
| | - Jérôme Le Pavec
- Department of Respiratory Diseases, Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Paris, France
| | - Andrew Fisher
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
- Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
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18
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Luo X, Du G, Long Y, Zheng M, Chen B, Li W, Yan G, Qi Z, Lan T. Programmed Death Ligand-1-Overexpressing Donor Exosomes Mediate Donor-Specific Immunosuppression by Delivering Co-Inhibitory Signals to Donor-Specific T Cells. Adv Healthc Mater 2023; 12:e2300670. [PMID: 37220874 DOI: 10.1002/adhm.202300670] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/21/2023] [Indexed: 05/25/2023]
Abstract
Programmed death ligand-1 (PD-L1) and donor antigens are critical for donor immature dendritic cells (DCs) targeting donor-specific T cells to induce transplant tolerance. This study aims to clarify whether DC-derived exosomes (DEX) with donor antigens (H2b) and high levels of PD-L1 expression (DEXPDL1+ ) can help to suppress graft rejection. In this study, it is demonstrated that DEXPDL1+ presents donor antigens, as well as PD-L1 co-inhibitory signals, directly or semi-directly via DCs to H2b-reactive T cells. This dual signal presentation can prolong the survival of heart grafts from B6 (H2b) mice but not from C3H (H2k) mice by inhibiting T cell activation, inducing activated T cell apoptosis, and modulating the balance of T cell differentiation from inflammatory to regulatory. Additionally, even though DEXPDL1+ treatment cannot induce tolerance after short-term treatment, this study provides a new vehicle for presenting co-inhibitory signals to donor-specific T cells. This novel strategy may facilitate the realization of donor-specific tolerance via the further optimization of drug-loading combinations and therapeutic regimens to elevate their killing ability.
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Affiliation(s)
- Xuewei Luo
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
- School of Medicine, Xiamen University, Xiamen, 361005, P. R. China
| | - Guicheng Du
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
| | - Yufei Long
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
- Medicinal College of Guangxi University, Nanning, Guangxi Province, 530004, P. R. China
| | - Mengchao Zheng
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
- Medicinal College of Guangxi University, Nanning, Guangxi Province, 530004, P. R. China
| | - Bingye Chen
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
| | - Weiting Li
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
| | - Guoliang Yan
- School of Medicine, Xiamen University, Xiamen, 361005, P. R. China
| | - Zhongquan Qi
- Medicinal College of Guangxi University, Nanning, Guangxi Province, 530004, P. R. China
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, 361023, P. R. China
- Wuzhou Workers' Hospital, No. 1, South 3rd Lane, Gaodi Road, Wanxiu District Wuzhou, Guangxi, 543000, P. R. China
| | - Tianshu Lan
- Institute of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian Province, 361023, P. R. China
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, 361023, P. R. China
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19
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Bansal S, Arjuna A, Franz B, Guerrero-Alba A, Canez J, Fleming T, Rahman M, Hachem R, Mohanakumar T. Extracellular vesicles: a potential new player in antibody-mediated rejection in lung allograft recipients. FRONTIERS IN TRANSPLANTATION 2023; 2:1248987. [PMID: 38993876 PMCID: PMC11235353 DOI: 10.3389/frtra.2023.1248987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/22/2023] [Indexed: 07/13/2024]
Abstract
Identification of recipients with pre-existing antibodies and cross-matching of recipient sera with donor lymphocytes have reduced the incidence of antibody-mediated rejection (AMR) after human lung transplantation. However, AMR is still common and requires not only immediate intervention but also has long-term consequences including an increased risk of chronic lung allograft dysfunction (CLAD). The mechanisms resulting in AMR remain largely unknown due to the variation in clinical and histopathological features among lung transplant recipients; however, several reports have demonstrated a strong association between the development of antibodies against mismatched donor human leucocyte antigens [donor-specific antibodies (DSAs)] and AMR. In addition, the development of antibodies against lung self-antigens (K alpha1 tubulin and collagen V) also plays a vital role in AMR pathogenesis, either alone or in combination with DSAs. In the current article, we will review the existing literature regarding the association of DSAs with AMR, along with clinical diagnostic features and current treatment options for AMR. We will also discuss the role of extracellular vesicles (EVs) in the immune-related pathogenesis of AMR, which can lead to CLAD.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Ashwini Arjuna
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Brian Franz
- HLA Laboratory, Vitalant, Phoenix, AZ, United States
| | - Alexa Guerrero-Alba
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Jesse Canez
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Mohammad Rahman
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Ramsey Hachem
- Department of Surgery, Washington University, St. Louis, MO, United States
| | - T. Mohanakumar
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
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20
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Cuadrado-Payán E, Ramírez-Bajo MJ, Bañón-Maneus E, Rovira J, Diekmann F, Revuelta I, Cucchiari D. Physiopathological role of extracellular vesicles in alloimmunity and kidney transplantation and their use as biomarkers. Front Immunol 2023; 14:1154650. [PMID: 37662919 PMCID: PMC10469977 DOI: 10.3389/fimmu.2023.1154650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 07/21/2023] [Indexed: 09/05/2023] Open
Abstract
Antibody-mediated rejection is the leading cause of kidney graft dysfunction. The process of diagnosing it requires the performance of an invasive biopsy and subsequent histological examination. Early and sensitive biomarkers of graft damage and alloimmunity are needed to identify graft injury and eventually limit the need for a kidney biopsy. Moreover, other scenarios such as delayed graft function or interstitial fibrosis and tubular atrophy face the same problem. In recent years, interest has grown around extracellular vesicles, specifically exosomes actively secreted by immune cells, which are intercellular communicators and have shown biological significance. This review presents their potential as biomarkers in kidney transplantation and alloimmunity.
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Affiliation(s)
- Elena Cuadrado-Payán
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
| | - María José Ramírez-Bajo
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Insituto de Salud Carlos III, Madrid, Spain
| | - Elisenda Bañón-Maneus
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Insituto de Salud Carlos III, Madrid, Spain
| | - Jordi Rovira
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Insituto de Salud Carlos III, Madrid, Spain
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Insituto de Salud Carlos III, Madrid, Spain
| | - Ignacio Revuelta
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Insituto de Salud Carlos III, Madrid, Spain
| | - David Cucchiari
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), Barcelona, Spain
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21
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Saravanan PB, Kalivarathan J, Khan F, Shah R, Levy MF, Kanak MA. Exosomes in transplantation: Role in allograft rejection, diagnostic biomarker, and therapeutic potential. Life Sci 2023; 324:121722. [PMID: 37100379 DOI: 10.1016/j.lfs.2023.121722] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/10/2023] [Accepted: 04/19/2023] [Indexed: 04/28/2023]
Abstract
Exosomes are 50-200 nm-sized extracellular vesicles that are secreted by cells to transfer signals and communicate with other cells. Recent research has revealed that allograft-specific exosomes containing proteins, lipids, and genetic materials are released into circulation post-transplantation which are powerful indicators of graft failure in solid-organ and tissue transplantations. The macromolecular content of exosomes released by the allograft and the immune cells serve as potential biomarkers for assessing the function and the acceptance/rejection status of the transplanted grafts. Identifying these biomarkers could aid in the development of therapeutic strategies to improve graft longevity. Exosomes can be used to deliver therapeutic agonists/antagonists to grafts and prevent rejection. Inducing long-term graft tolerance has been demonstrated in many studies using exosomes from immunomodulatory cells such as immature DCs, T regulatory cells, and MSCs. The use of graft-specific exosomes for targeted drug therapy has the potential to reduce the unwanted side effects of immunosuppressive drugs. Overall, in this review, we have explored the critical role of exosomes in the recognition and cross-presentation of donor organ-specific antigens during allograft rejection. Additionally, we have discussed the potential of exosomes as a biomarker for monitoring graft function and damage, as well as their potential therapeutic applications in mitigating allograft rejection.
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Affiliation(s)
| | - Jagan Kalivarathan
- VCU Hume-Lee Transplant Institute, VCU health system, Richmond, VA, United States of America
| | - Faizaan Khan
- Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
| | - Rashi Shah
- Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
| | - Marlon F Levy
- VCU Hume-Lee Transplant Institute, VCU health system, Richmond, VA, United States of America; Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
| | - Mazhar A Kanak
- VCU Hume-Lee Transplant Institute, VCU health system, Richmond, VA, United States of America; Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
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22
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Extracellular Vesicles: The Future of Diagnosis in Solid Organ Transplantation? Int J Mol Sci 2023; 24:ijms24065102. [PMID: 36982182 PMCID: PMC10048932 DOI: 10.3390/ijms24065102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/10/2023] Open
Abstract
Solid organ transplantation (SOT) is a life-saving treatment for end-stage organ failure, but it comes with several challenges, the most important of which is the existing gap between the need for transplants and organ availability. One of the main concerns in this regard is the lack of accurate non-invasive biomarkers to monitor the status of a transplanted organ. Extracellular vesicles (EVs) have recently emerged as a promising source of biomarkers for various diseases. In the context of SOT, EVs have been shown to be involved in the communication between donor and recipient cells and may carry valuable information about the function of an allograft. This has led to an increasing interest in exploring the use of EVs for the preoperative assessment of organs, early postoperative monitoring of graft function, or the diagnosis of rejection, infection, ischemia-reperfusion injury, or drug toxicity. In this review, we summarize recent evidence on the use of EVs as biomarkers for these conditions and discuss their applicability in the clinical setting.
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23
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Shiotani T, Sugimoto S, Tomioka Y, Yamamoto H, Tanaka S, Miyoshi K, Suzawa K, Shien K, Yamamoto H, Okazaki M, Toyooka S. Diagnostic value of circulating microRNA-21 in chronic lung allograft dysfunction after bilateral cadaveric and living-donor lobar lung transplantation. Heliyon 2023; 9:e14903. [PMID: 37025782 PMCID: PMC10070710 DOI: 10.1016/j.heliyon.2023.e14903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 03/11/2023] [Accepted: 03/21/2023] [Indexed: 03/28/2023] Open
Abstract
Background MicroRNAs (miRNAs) involved in the pathogenesis of pulmonary fibrosis have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). We investigated the role of circulating miRNAs in the diagnosis of CLAD after bilateral LT, including cadaveric LT (CLT) and living-donor lobar LT (LDLLT). Methods The subjects of this retrospective study were 37 recipients of bilateral CLT (n = 23) and LDLLT (n = 14), and they were divided into a non-CLAD group (n = 24) and a CLAD group (n = 13). The plasma miRNA levels of the two groups were compared, and correlations between their miRNAs levels and percent baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) values were calculated from one year before to one year after the diagnosis of CLAD. Results The plasma levels of both miR-21 and miR-155 at the time of the diagnosis of CLAD were significantly higher in the CLAD group than in the non-CLAD group (miR-21, P = 0.0013; miR-155, P = 0.042). The miR-21 levels were significantly correlated with the percent baseline FEV1, FVC, and TLC value of one year before and at the time of diagnosis of CLAD (P < 0.05). A receiver operating characteristic curve analysis of the performance of miR-21 levels in the diagnosis of CLAD yielded an area under the curve of 0.89. Conclusion Circulating miR-21 appears to be of potential value in diagnosing CLAD after bilateral LT.
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Affiliation(s)
- Toshio Shiotani
- Organ Transplant Center, Okayama University Hospital, Okayama, Japan
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Seiichiro Sugimoto
- Organ Transplant Center, Okayama University Hospital, Okayama, Japan
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
- Corresponding author. Organ Transplant Center, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Yasuaki Tomioka
- Organ Transplant Center, Okayama University Hospital, Okayama, Japan
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Haruchika Yamamoto
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Shin Tanaka
- Organ Transplant Center, Okayama University Hospital, Okayama, Japan
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Kentaroh Miyoshi
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Ken Suzawa
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Kazuhiko Shien
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Hiromasa Yamamoto
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Mikio Okazaki
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Shinichi Toyooka
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
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24
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Olson MT, Liu W, Mohanakumar T, Bremner RM. A potential mechanism by which aspiration of duodenogastric fluid augments the risk for bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg 2023; 165:e23-e37. [PMID: 35428458 DOI: 10.1016/j.jtcvs.2022.03.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 03/04/2022] [Accepted: 03/12/2022] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Aspiration of duodenogastric refluxate may damage the respiratory epithelium of lung allografts in transplant recipients. We sought to define a mechanism by which aspiration of duodenogastric fluid augments the risk of bronchiolitis obliterans syndrome after lung transplant in a murine model. METHODS We analyzed the immunological effects of acute aspiration of duodenogastric fluid (0.5 mL/kg) on transplant naive (strain DBA/2J) and transplanted mice (strain B6D2F1/J to strain DBA/2J). Serum antibodies to the lung self-antigens (SAgs) K-alpha1 tubulin and collagen-V were determined by enzyme-linked immunosorbent assay. Exosomes were isolated from serum, and immunoblot membranes were probed for antibodies to lung SAgs. Lung sections were assessed for fibrotic burden and obliterative bronchiolitis lesions by histologic and immunohistochemical analyses, including trichrome staining. RESULTS Transplanted mice that received duodenogastric fluid developed higher levels of antibodies to the lung SAgs K-alpha1 tubulin and collagen-V and exosomes with lung SAgs on posttransplant days 14 and 28 than transplanted mice with sham aspiration or transplant naive mice (with and without aspiration). All lung allografts demonstrated severe grade A4 rejection on posttransplant day 14, with the highest mean fibrotic burden and mean number of obliterative bronchiolitis-like lesions per microscopic field on day 28 in recipients with aspiration. CONCLUSIONS This study links aspiration of duodenogastric fluid after lung transplant to higher autoimmune responses to lung SAgs and the release of circulating exosomes with lung SAgs, which together promote sustained immune responses leading to extensive lung parenchymal damage and, ultimately, severe obliterative bronchiolitis-the histologic hallmark of bronchiolitis obliterans syndrome.
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Affiliation(s)
- Michael T Olson
- University of Arizona College of Medicine-Phoenix Campus, Phoenix, Ariz; Norton Thoracic Institute Research Laboratory, St Joseph's Hospital and Medical Center, Phoenix, Ariz; Division of Thoracic Surgery, Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, Ariz
| | - Wei Liu
- Norton Thoracic Institute Research Laboratory, St Joseph's Hospital and Medical Center, Phoenix, Ariz
| | - Thalachallour Mohanakumar
- Norton Thoracic Institute Research Laboratory, St Joseph's Hospital and Medical Center, Phoenix, Ariz
| | - Ross M Bremner
- Division of Thoracic Surgery, Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, Ariz.
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25
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Chen L, Yang J, Xu G, Wu Y. Potential Value and Application of Liquid Biopsy in Tumor, Neurodegeneration, and Muscle Degenerative Diseases. Methods Mol Biol 2023; 2695:317-335. [PMID: 37450129 DOI: 10.1007/978-1-0716-3346-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Liquid biopsy provides a promising alternative for the detection of disease-specific markers due to its superior noninvasive and original tissue representativeness. Liquid biopsies have a wide range of health and disease applications involving components ranging from circulating cells to acellular nucleic acid molecules and other metabolites. Here, we review the different components of liquid biopsy and investigate the most advanced noninvasive methods for detecting these components as well as their existing problems and trends. In particular, we emphasize the importance of analyzing liquid biopsy data from extracellular vesicles and small nucleic acids in neurological and muscle degeneration, with the aim of using this technique to enhance personalized healthcare. Although previous reviews have focused on cancer, this review mainly emphasizes the potential application of extracellular vesicles and microRNAs in liquid biopsy in neurodegeneration and muscle degeneration.
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Affiliation(s)
- Lin Chen
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei, People's Republic of China
| | - Jun Yang
- Jianghan University Library, Wuhan, Hubei, People's Republic of China
| | - Guodong Xu
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei, People's Republic of China
| | - Yuxiang Wu
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei, People's Republic of China.
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26
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HEIDARI FATEMEH, SEYEDEBRAHIMI REIHANEH, YANG PIAO, FARSANI MOHSENESLAMI, ABABZADEH SHIMA, KALHOR NASER, MANOOCHEHRI HAMED, SHEYKHHASAN MOHSEN, AZIMZADEH MARYAM. Exosomes in viral infection: Effects for pathogenesis and treatment strategies. BIOCELL 2023; 47:2597-2608. [DOI: 10.32604/biocell.2023.043351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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27
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Direct detection of circulating donor-derived extracellular vesicles in kidney transplant recipients. Sci Rep 2022; 12:21973. [PMID: 36539446 PMCID: PMC9768203 DOI: 10.1038/s41598-022-26580-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Extracellular vesicles (EVs) are tissue-specific particles containing valuable diagnostic information. However, single EV analysis in blood is challenging due to their physical properties, the molecular complexity of plasma, and a lack of robust data interpretation methods. We assess the applicability of our recently-developed calibrated Imaging Flow Cytometry (IFCM)-based methodology to detect/characterize circulating tissue-specific EV subsets in the clinical setting of kidney transplantation. Platelet-poor plasma was generated from 36 HLA-A3 mismatched donor (HLA-A3 +) and kidney transplant recipients (KTRs; HLA-A3-). Samples taken before transplantation, 3 days, 7 days, and 6 months after transplantation as well as before 'for-cause' kidney transplant biopsies were stained with anti-CD9 (plasma EV-marker) and anti-HLA-A3. Before transplantation, no significant differences in total CD9 + EV concentrations were detected between donor and KTR samples. Tissue-specific EVs were identified as CD9 + HLA-A3 + . Serial dilution experiments of HLA-A3 + in HLA-A3- PPP showed that single CD9 + HLA-A3 + EVs were detectable down to ~ 1% above the recipient 'self-signal'. After transplantation, CD9 + HLA-A3 + EVs were detected above pre-transplantation concentrations in individuals with stable allograft function, but not in individuals with allograft dysfunction. These results demonstrate the applicability of our calibrated IFCM-based methodology in the direct detection of tissue-specific EV subsets in clinical samples. We believe that this EV methodology is applicable in a variety of clinical contexts.
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28
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Yang W, Cerier EJ, Núñez-Santana FL, Wu Q, Yan Y, Kurihara C, Liu X, Yeldandi A, Khurram N, Avella-Patino D, Sun H, Budinger GS, Kreisel D, Mohanakumar T, Lecuona E, Bharat A. IL-1β-dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction. J Clin Invest 2022; 132:157975. [PMID: 36250462 PMCID: PMC9566897 DOI: 10.1172/jci157975] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1β-mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - G.R. Scott Budinger
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Daniel Kreisel
- Departments of Surgery, Pathology & Immunology, Washington University, St. Louis, Missouri, USA
| | | | | | - Ankit Bharat
- Division of Thoracic Surgery
- Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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29
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Bos S, Milross L, Filby AJ, Vos R, Fisher AJ. Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle. Eur Respir Rev 2022; 31:31/165/220060. [PMID: 35896274 DOI: 10.1183/16000617.0060-2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/19/2022] [Indexed: 11/05/2022] Open
Abstract
Lung transplantation is the optimal treatment for selected patients with end-stage chronic lung diseases. However, chronic lung allograft dysfunction remains the leading obstacle to improved long-term outcomes. Traditionally, lung allograft rejection has been considered primarily as a manifestation of cellular immune responses. However, in reality, an array of complex, interacting and multifactorial mechanisms contribute to its emergence. Alloimmune-dependent mechanisms, including T-cell-mediated rejection and antibody-mediated rejection, as well as non-alloimmune injuries, have been implicated. Moreover, a role has emerged for autoimmune responses to lung self-antigens in the development of chronic graft injury. The aim of this review is to summarise the immune processes involved in the pathogenesis of chronic lung allograft dysfunction, with advanced insights into the role of innate immune pathways and crosstalk between innate and adaptive immunity, and to identify gaps in current knowledge.
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Affiliation(s)
- Saskia Bos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.,Institute of Transplantation, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Luke Milross
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
| | - Andrew J Filby
- Flow Cytometry Core and Innovation, Methodology and Application Research Theme, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Robin Vos
- Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Dept of Respiratory Diseases, Leuven, Belgium
| | - Andrew J Fisher
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK .,Institute of Transplantation, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
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30
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Regenerative mesenchymal stem c
ell‐derived
extracellular vesicles: A potential alternative to c
ell‐based
therapy in viral infection and disease damage control. WIREs Mech Dis 2022; 14:e1574. [DOI: 10.1002/wsbm.1574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 05/24/2022] [Indexed: 11/07/2022]
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31
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Krishnan A, Gangadaran P, Chavda VP, Jogalekar MP, Muthusamy R, Valu D, Vadivalagan C, Ramani P, Laishevtcev A, Katari NK, Ahn BC. Convalescent serum-derived exosomes: Attractive niche as COVID-19 diagnostic tool and vehicle for mRNA delivery. Exp Biol Med (Maywood) 2022; 247:1244-1252. [PMID: 35549570 PMCID: PMC9379609 DOI: 10.1177/15353702221092984] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The spread of SARS-CoV-2 over the entire world is more commonly known as COVID-19. COVID-19 has impacted society in every aspect of routine life. SARS-CoV-2 infection is often misdiagnosed as influenza or seasonal upper respiratory tract viral infections. General diagnostic tools can detect the viral antigen or isotypes of antibodies. However, inter- and intraindividual variations in antibody levels can cause false negatives in antibody immunoassays. On the contrary, the false-positive test results can also occur due to either cross-reactivity of the viral antigens or some other patient-related autoimmune factors. There is need for a cogent diagnostic tool with more specificity, selectivity, and reliability. Here, we have described the potential of convalescent serum-derived exosome as a diagnostic tool for the detection of SARS-CoV-2, even in asymptomatic patients, which is a limitation for currently practiced diagnostic tests throughout the globe. In addition, its potential as a vehicle for messenger RNA (mRNA) delivery is also emphasized.
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Affiliation(s)
- Anand Krishnan
- Department of Chemical Pathology, School of Pathology, Faculty of Health Sciences, University of the Free State, Bloemfontein 9300, South Africa
- Department of Chemical Pathology, School of Pathology, National Health Laboratory Services, Bloemfontein 9301, South Africa
| | - Prakash Gangadaran
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Vivek P Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad 380009, India
| | - Manasi P Jogalekar
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Ramesh Muthusamy
- Department of Pharmaceutical Analysis, Omega College of Pharmacy, Hyderabad 501301, India
| | - Disha Valu
- Research and Development, Intas Pharmaceuticals Ltd. (Biopharma Division), Ahmedabad 382213, India
| | - Chithravel Vadivalagan
- Molecular Cell Physiology Laboratory, Department of Biochemistry, School of Medicine, AKFA University, Tashkent 100042, Uzbekistan
| | - Prasanna Ramani
- Dhanvanthri Lab, Department of Sciences, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Coimbatore 641112, India
- Center of Excellence in Advanced Materials & Green Technologies (CoE–AMGT), Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Coimbatore 641112, India
| | - Alexey Laishevtcev
- Federal Research Center—All-Russian Scientific Research Institute of Experimental Veterinary Medicine named after K.I. Skryabin and Y.R. Kovalenko of the Russian Academy of Sciences, Moscow 117218, Russia
- Laboratory of Biocontrol and Antimicrobial Resistance, Orel State University named after I.S. Turgenev, Orel 302026, Russia
| | - Naresh Kumar Katari
- Department of Chemistry, GITAM (Deemed to be University), Hyderabad 502329, India
| | - Byeong-Cheol Ahn
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
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32
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Ravichandran R, Bansal S, Rahman M, Sureshbabu A, Sankpal N, Fleming T, Bharat A, Mohanakumar T. Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations. Front Immunol 2022; 13:861583. [PMID: 35572510 PMCID: PMC9094427 DOI: 10.3389/fimmu.2022.861583] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Transplantation is a treatment option for patients diagnosed with end-stage organ diseases; however, long-term graft survival is affected by rejection of the transplanted organ by immune and nonimmune responses. Several studies have demonstrated that both acute and chronic rejection can occur after transplantation of kidney, heart, and lungs. A strong correlation has been reported between de novo synthesis of donor-specific antibodies (HLA-DSAs) and development of both acute and chronic rejection; however, some transplant recipients with chronic rejection do not have detectable HLA-DSAs. Studies of sera from such patients demonstrate that immune responses to tissue-associated antigens (TaAgs) may also play an important role in the development of chronic rejection, either alone or in combination with HLA-DSAs. The synergistic effect between HLA-DSAs and antibodies to TaAgs is being established, but the underlying mechanism is yet to be defined. We hypothesize that HLA-DSAs damage the transplanted donor organ resulting in stress and leading to the release of extracellular vesicles, which contribute to chronic rejection. These vesicles express both donor human leukocyte antigen (HLA) and non-HLA TaAgs, which can activate antigen-presenting cells and lead to immune responses and development of antibodies to both donor HLA and non-HLA tissue-associated Ags. Extracellular vesicles (EVs) are released by cells under many circumstances due to both physiological and pathological conditions. Primarily employing clinical specimens obtained from human lung transplant recipients undergoing acute or chronic rejection, our group has demonstrated that circulating extracellular vesicles display both mismatched donor HLA molecules and lung-associated Ags (collagen-V and K-alpha 1 tubulin). This review focuses on recent studies demonstrating an important role of antibodies to tissue-associated Ags in the rejection of transplanted organs, particularly chronic rejection. We will also discuss the important role of extracellular vesicles released from transplanted organs in cross-talk between alloimmunity and autoimmunity to tissue-associated Ags after solid organ transplantation.
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Affiliation(s)
| | - Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Mohammad Rahman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Angara Sureshbabu
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Narendra Sankpal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Ankit Bharat
- Department of Surgery-Thoracic, Northwestern University, Chicago, IL, United States
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33
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Rutman AK, Negi S, Saberi N, Khan K, Tchervenkov J, Paraskevas S. Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios. Front Immunol 2022; 13:784374. [PMID: 35281056 PMCID: PMC8906931 DOI: 10.3389/fimmu.2022.784374] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Delayed graft function (DGF) in kidney transplantation is associated with ischemic injury and carries long term functional and immunological risks. Extracellular vesicles (EV) released from allografts may signal a degree of ischemic stress, and are thought to play an important role in the development of anti-donor immunity. Here, we show that kidney perfusate-derived extracellular vesicles (KP-EV) express donor-specific human leukocyte antigen. KP-EV from kidneys that experience DGF increase the T-helper 17 (Th17) to T-regulatory (Treg) ratio in third party peripheral blood mononuclear cells to a greater degree than those from kidneys with immediate function. We report miR-218-5p upregulation in KP-EV of kidney transplant recipients with DGF. Levels of miR-218-5p in KP-EV inversely correlated with recipient eGFR at multiple time points following transplantation. Additionally, the degree of increase in Th17/Treg ratio by KP-EV positively correlated with miR-218-5p expression in KP-EV samples. Taken together, these data provide evidence that KP-EV may contribute to modulating immune responses in transplant recipients. This could lead to novel intervention strategies to inhibit DGF in order to improve graft function and survival.
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Affiliation(s)
- Alissa K Rutman
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Sarita Negi
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Nasim Saberi
- Department of Surgery, McGill University, Montréal, QC, Canada
| | - Kashif Khan
- Division of Cardiology and Cardiac Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - Jean Tchervenkov
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Steven Paraskevas
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
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34
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Habertheuer A, Ram C, Schmierer M, Chatterjee S, Hu R, Freas A, Zielinski P, Rogers W, Silvestro EM, McGrane M, Moore JS, Korutla L, Siddiqui S, Xin Y, Rizi R, Qin Tao J, Kreisel D, Naji A, Ochiya T, Vallabhajosyula P. Circulating Donor Lung-specific Exosome Profiles Enable Noninvasive Monitoring of Acute Rejection in a Rodent Orthotopic Lung Transplantation Model. Transplantation 2022; 106:754-766. [PMID: 33993180 DOI: 10.1097/tp.0000000000003820] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND There is a critical need for development of biomarkers to noninvasively monitor for lung transplant rejection. We investigated the potential of circulating donor lung-specific exosome profiles for time-sensitive diagnosis of acute rejection in a rat orthotopic lung transplant model. METHODS Left lungs from Wistar transgenic rats expressing human CD63-GFP, an exosome marker, were transplanted into fully MHC-mismatched Lewis recipients or syngeneic controls. Recipient blood was collected between 4 h and 10 d after transplantation, and plasma was processed for exosome isolation by size exclusion column chromatography and ultracentrifugation. Circulating donor exosomes were profiled using antihuman CD63 antibody quantum dot on the nanoparticle detector and via GFP trigger on the nanoparticle flow cytometer. RESULTS In syngeneic controls, steady-state levels of circulating donor exosomes were detected at all posttransplant time points. Allogeneic grafts lost perfusion by day 8, consistent with acute rejection. Levels of circulating donor exosomes peaked on day 1, decreased significantly by day 2, and then reached baseline levels by day 3. Notably, decrease in peripheral donor exosome levels occurred before grafts had histological evidence of acute rejection. CONCLUSIONS Circulating donor lung-specific exosome profiles enable an early detection of acute rejection before histologic manifestation of injury to the pulmonary allograft. As acute rejection episodes are a major risk factor for the development of chronic lung allograft dysfunction, this biomarker may provide a novel noninvasive diagnostic platform that can translate into earlier therapeutic intervention for lung transplant patients.
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Affiliation(s)
- Andreas Habertheuer
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
- Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Chirag Ram
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | - Shampa Chatterjee
- Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Robert Hu
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Andrew Freas
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Patrick Zielinski
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Wade Rogers
- Still Pond Cytomics LLC, West Chester, PA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Eva M Silvestro
- Still Pond Cytomics LLC, West Chester, PA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | - Jonni S Moore
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Laxminarayana Korutla
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
- Division of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT
| | - Sarmad Siddiqui
- Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Yi Xin
- Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Rahim Rizi
- Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jian Qin Tao
- Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Daniel Kreisel
- Departments of Surgery, Pathology & Immunology, Washington University, St. Louis, MI
| | - Ali Naji
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan
| | - Prashanth Vallabhajosyula
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
- Division of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT
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35
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Baan CC, Boer K. Extracellular Vesicles: Promising Candidates in Transplant Function Monitoring. Transplantation 2022; 106:698-699. [PMID: 33979316 DOI: 10.1097/tp.0000000000003821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Carla C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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36
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Sailliet N, Ullah M, Dupuy A, Silva AKA, Gazeau F, Le Mai H, Brouard S. Extracellular Vesicles in Transplantation. Front Immunol 2022; 13:800018. [PMID: 35185891 PMCID: PMC8851566 DOI: 10.3389/fimmu.2022.800018] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) have been extensively studied in the last two decades. It is now well documented that they can actively participate in the activation or regulation of immune system functions through different mechanisms, the most studied of which include protein–protein interactions and miRNA transfers. The functional diversity of EV-secreting cells makes EVs potential targets for immunotherapies through immune cell-derived EV functions. They are also a potential source of biomarkers of graft rejection through donor cells or graft environment-derived EV content modification. This review focuses on preclinical studies that describe the role of EVs from different cell types in immune suppression and graft tolerance and on the search for biomarkers of rejection.
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Affiliation(s)
- Nicolas Sailliet
- Nantes Université, INSERM, Centeer for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Matti Ullah
- MSC-med, INSERM U7057, Universite de Paris, Paris, France
| | - Amandine Dupuy
- Nantes Université, INSERM, Centeer for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | | | | | - Hoa Le Mai
- Nantes Université, INSERM, Centeer for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Sophie Brouard
- Nantes Université, INSERM, Centeer for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France.,Labex IGO, Nantes, France
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37
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Silva TD, Voisey J, Hopkins P, Apte S, Chambers D, O'Sullivan B. Markers of rejection of a lung allograft: state of the art. Biomark Med 2022; 16:483-498. [PMID: 35315284 DOI: 10.2217/bmm-2021-1013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Chronic lung allograft dysfunction (CLAD) affects approximately 50% of all lung transplant recipients by 5 post-operative years and is the leading cause of death in lung transplant recipients. Early CLAD diagnosis or ideally prediction of CLAD is essential to enable early intervention before significant lung injury occurs. New technologies have emerged to facilitate biomarker discovery, including epigenetic modification and single-cell RNA sequencing. This review examines new and existing technologies for biomarker discovery and the current state of research on biomarkers for identifying lung transplant rejection.
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Affiliation(s)
- Tharushi de Silva
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia
| | - Joanne Voisey
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
| | - Peter Hopkins
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| | - Simon Apte
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| | - Daniel Chambers
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| | - Brendan O'Sullivan
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
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38
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Rahman M, Ravichandran R, Bansal S, Sanborn K, Bowen S, Eschbacher J, Sureshbabu A, Fleming T, Bharat A, Walia R, Hachem R, Bremner RM, Smith MA, Mohanakumar T. Novel role for tumor suppressor gene, liver kinase B1, in epithelial-mesenchymal transition leading to chronic lung allograft dysfunction. Am J Transplant 2022; 22:843-852. [PMID: 34859569 DOI: 10.1111/ajt.16903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 01/25/2023]
Abstract
Epithelial-mesenchymal transition (EMT) has been implicated to play a role in chronic lung allograft dysfunction (CLAD). Liver kinase B1 (LKB1), a tumor suppressor gene, can regulate EMT. However, its role in CLAD development following lung transplantation remains unknown. Using qRT-PCR, biopsies from lung transplant recipients with bronchiolitis obliterans syndrome (BOS) demonstrated significant downregulation of LKB1 (p = .0001), compared to stable biopsies. To determine the role of LKB1 in EMT development, we analyzed EMT in human bronchial epithelial cell line BEAS-2B. Knockdown of LKB1 by siRNA significantly dysregulated mesenchymal markers expression in BEAS-2B cells. Following incubation of human primary bronchial epithelial cell or BEAS-2B cells with exosomes isolated from BOS or stable lung transplant recipients, LKB1 expression was inhibited when incubated with BOS-exosome. Incubation with BOS-exosomes also decreased LKB1 expression and induced EMT markers in air-liquid interface culture method. Our results provide novel evidence that exosomes released from transplanted lungs undergoing chronic rejection are associated with inactivated tumor suppressor gene LKB1 and this loss induces EMT leading to the pathogenesis of CLAD following human lung transplantation.
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Affiliation(s)
- Mohammad Rahman
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | | | - Sandhya Bansal
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | - Kristina Sanborn
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | - Sara Bowen
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | - Jennifer Eschbacher
- St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, Arizona
| | - Angara Sureshbabu
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | - Timothy Fleming
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | | | - Rajat Walia
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | - Ramsey Hachem
- Washington University School of Medicine, St. Louis, Missouri
| | - Ross M Bremner
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
| | - Michael A Smith
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, Arizona
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39
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Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis. Mol Neurobiol 2022; 59:2441-2455. [PMID: 35083659 PMCID: PMC9016041 DOI: 10.1007/s12035-021-02705-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/14/2021] [Indexed: 12/13/2022]
Abstract
Encephalitis mediated by autoantibodies against neuronal antigens and herpes simplex encephalitis (HSE) are seemingly separate causes of encephalopathy in adults. Autoimmune encephalitis (AE) is autoimmune in origin, and herpes simplex encephalitis is infectious. The purpose of this study was to examine the role of cerebrospinal fluid (CSF) exosomes from patients with antibody-positive AE and HSE. Towards this, exosomes were isolated from CSF from 13 patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, 11 patients with anti-gamma-aminobutyric acid-B (GABAB) receptor encephalitis, 9 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, and 12 control individuals negative of antibodies against neuronal autoantigens. There were ten miRNAs highly expressed in patients with anti-NMDAR encephalitis compared to those in control subjects. Eight miRNAs were found to be lower expressed in anti-NMDAR encephalitis CSF-derived exosomes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by AE differential expressed exosomic miRNAs demonstrated that AE-related exosomic miRNAs may participate as a feedback regulation in cancer development. In addition, the exosome concentration in CSF of 9 HSE patients was significantly higher compared to those from 9 HSV( −) patients. This observation was consistent with the results that exosome concentration was found to be higher in the animal model which was inoculated intranasally with HSV-1 compared to controls. Furthermore, western blot demonstrated that the subunits of NMDAR, GABABR, and AMPAR were detected highly expressed in exosomes derived from sera of HSV-1-treated animal model compared to controls. More importantly, exosomes isolated from CSF of HSE patients contained higher expression levels of two miRNAs encoded by HSV, miR-H2-3p, and miR-H4-3p compared to those from HSV( −) patients. In summary, HSV may trigger brain autoimmunity in HSE by presentation of surface autoantigens via exosomes.
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40
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Ranganathan M, Rahman M, Ganesh S, D'Souza DC, Skosnik PD, Radhakrishnan R, Pathania S, Mohanakumar T. Analysis of circulating exosomes reveals a peripheral signature of astrocytic pathology in schizophrenia. World J Biol Psychiatry 2022; 23:33-45. [PMID: 33821753 DOI: 10.1080/15622975.2021.1907720] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Extracellular vesicles, including exosomes, cross the blood brain barrier with their contents intact and can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. This study aimed to examine neuropathology-relevant protein biomarkers in circulating plasma-derived exosomes from patients with schizophrenia and age- and sex-matched healthy controls. METHODS Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo protein (glial fibrillary acid protein[GFAP], synaptophysin, and α-II-Spectrin) immunopositivity was examined using Western blot analyses with band intensity quantified. Methods were consistent with the 'Minimal information for studies of extracellular vesicles 2018' (MISEV2018) guidelines. RESULTS Exosomal GFAP concentration was significantly higher and α-II-Spectrin expression significantly lower in plasma obtained from schizophrenia patients. No group differences were observed between in plasma exosomal concentration and size or in CD9, calnexin, or synaptophysin levels. CONCLUSIONS Our results demonstrate a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesised astroglial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.
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Affiliation(s)
- Mohini Ranganathan
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,VA Connecticut Healthcare System, West Haven, CT, USA
| | - Mohamed Rahman
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, AZ, USA
| | - Suhas Ganesh
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Deepak C D'Souza
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,VA Connecticut Healthcare System, West Haven, CT, USA
| | - Patrick D Skosnik
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,VA Connecticut Healthcare System, West Haven, CT, USA
| | - Rajiv Radhakrishnan
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Surbhi Pathania
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
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41
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Gupta S, Mazumder P. Exosomes as diagnostic tools. Adv Clin Chem 2022; 110:117-144. [DOI: 10.1016/bs.acc.2022.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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42
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Bansal S, Arjuna A, Perincheri S, Poulson C, Bremner RM, Smith MA, Tokman S, Mohanakumar T. Restrictive allograft syndrome vs bronchiolitis obliterans syndrome: Immunological and molecular characterization of circulating exosomes. J Heart Lung Transplant 2022; 41:24-33. [PMID: 34602310 PMCID: PMC11019888 DOI: 10.1016/j.healun.2021.09.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/16/2021] [Accepted: 09/02/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Chronic lung allograft dysfunction in lung transplant recipients (LTxRs) has 2 phenotypes: obstructive bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Our goal was to define distinct immunologic markers of exosomes from LTxRs with BOS or RAS. METHODS Plasma was collected from LTxRs with BOS (n = 18), RAS (n = 13), and from stable LTxRs (n = 5). Antibodies to lung self-antigens (SAgs) were determined by ELISA. Exosomes were isolated by ultracentrifugation. Donor specific antibodies to HLA were quantified using Luminex. Exosomes were characterized for lung SAgs, transcription factors, 20S proteasome, HLA class I and II, and polymeric immunoglobulin receptor protein using western blot. Exosome miRNA was analyzed using NanoString. The exosome-induced immune response was determined in mice. RESULTS LTxRs with RAS, but not BOS, had donor specific antibodies at diagnosis. CIITA, NFkB, polymeric immunoglobulin receptor protein, 20S proteasome, HLA-DQ, and HLA-DR were significantly higher in RAS exosomes than in BOS exosomes. RAS plasma had high levels of proinflammatory cytokines and distinct exosomal miRNA. Immunization of C57BL/6 mice with RAS exosomes showed severe inflammation and peribronchial fibrosis, whereas BOS exosomes induced patchy inflammation and fibrosis. CONCLUSION LTxRs with BOS or RAS had exosomes with distinct molecular and immunologic profiles. RAS samples had a higher concentration of proinflammatory factors, HLA class II, lung SAgs, and antibodies to HLA class II molecules, indicating severe allograft injury. Mice immunized with RAS exosomes developed lesions in airways, pleura, interlobular septum, and alveoli, whereas BOS exosomes induced mild to patchy inflammation with lung fibrosis.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
| | - Ashwini Arjuna
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
| | - Sudhir Perincheri
- Department of Pathology and Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Christin Poulson
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
| | - Ross M Bremner
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
| | - Michael A Smith
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
| | - Sofya Tokman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
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43
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Ravichandran R, Itabashi Y, Liu W, Bansal S, Rahman M, Poulson C, Fleming T, Bremner RM, Smith M, Mohanakumar T. A decline in club cell secretory proteins in lung transplantation is associated with release of natural killer cells exosomes leading to chronic rejection. J Heart Lung Transplant 2021; 40:1517-1528. [PMID: 34627707 PMCID: PMC11019779 DOI: 10.1016/j.healun.2021.08.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 08/06/2021] [Accepted: 08/30/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND In human lung transplant recipients, a decline in club cell secretory protein (CCSP) in bronchoalveolar lavage fluid has been associated with chronic lung allograft dysfunction (CLAD) as well as the induction of exosomes and immune responses that lead to CLAD. However, the mechanisms by which CCSP decline contributes to CLAD remain unknown. METHODS To define the mechanisms leading to CCSP decline and chronic rejection, we employed two mouse models: 1) chronic rejection after orthotopic single lung transplantation and 2) anti-major histocompatibility complex (MHC) class I-induced obliterative airway disease. RESULTS In the chronic rejection mouse model, we detected circulating exosomes with donor MHC (H2b) and lung self-antigens and also development of antibodies to H2b and lung self-antigens and then a decline in CCSP. Furthermore, DBA2 mice that received injections of these exosomes developed antibodies to donor MHC and lung self-antigens. In the chronic rejection mouse model, natural killer (NK) and CD8 T cells were the predominant graft-infiltrating cells on day 14 of rejection followed by exosomes containing NK cell-associated and cytotoxic molecules on day 14 and 28. When NK cells were depleted, exosomes with NK cell-associated and cytotoxic molecules as well as fibrosis decreased. CONCLUSIONS Induction of exosomes led to immune responses to donor MHC and lung self-antigens, resulting in CCSP decline, leading to NK cell infiltration and release of exosomes from NK cells. These results suggest a novel role for exosomes derived from NK cells in the pathogenesis of chronic lung allograft rejection.
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Affiliation(s)
| | | | - Wei Liu
- Norton Thoracic Institute, Phoenix, Arizona
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44
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Ravindranath MH, El Hilali F, Filippone EJ. The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection? Front Immunol 2021; 12:667834. [PMID: 34880853 PMCID: PMC8647190 DOI: 10.3389/fimmu.2021.667834] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 10/11/2021] [Indexed: 12/21/2022] Open
Abstract
Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).
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Affiliation(s)
- Mepur H. Ravindranath
- Department of Hematology and Oncology, Children’s Hospital, Los Angeles, CA, United States
- Terasaki Foundation Laboratory, Santa Monica, CA, United States
| | | | - Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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45
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Gołębiewska JE, Wardowska A, Pietrowska M, Wojakowska A, Dębska-Ślizień A. Small Extracellular Vesicles in Transplant Rejection. Cells 2021; 10:2989. [PMID: 34831212 PMCID: PMC8616261 DOI: 10.3390/cells10112989] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/31/2021] [Accepted: 10/31/2021] [Indexed: 12/28/2022] Open
Abstract
Small extracellular vesicles (sEV), which are released to body fluids (e.g., serum, urine) by all types of human cells, may stimulate or inhibit the innate and adaptive immune response through multiple mechanisms. Exosomes or sEV have on their surface many key receptors of immune response, including major histocompatibility complex (MHC) components, identical to their cellular origin. They also exhibit an ability to carry antigen and target leukocytes either via interaction with cell surface receptors or intracellular delivery of inflammatory mediators, receptors, enzymes, mRNAs, and noncoding RNAs. By the transfer of donor MHC antigens to recipient antigen presenting cells sEV may also contribute to T cell allorecognition and alloresponse. Here, we review the influence of sEV on the development of rejection or tolerance in the setting of solid organ and tissue allotransplantation. We also summarize and discuss potential applications of plasma and urinary sEV as biomarkers in the context of transplantation. We focus on the attempts to use sEV as a noninvasive approach to detecting allograft rejection. Preliminary studies show that both sEV total levels and a set of specific molecules included in their cargo may be an evidence of ongoing allograft rejection.
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Affiliation(s)
- Justyna E. Gołębiewska
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
| | - Anna Wardowska
- Department of Physiopathology, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
| | - Monika Pietrowska
- Centre for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland;
| | - Anna Wojakowska
- Institute of Bioorganic Chemistry Polish Academy of Sciences, 61-704 Poznań, Poland;
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
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Chuang HC, Chen MH, Chen YM, Yang HY, Ciou YR, Hsueh CH, Tsai CY, Tan TH. BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus. Theranostics 2021; 11:9953-9966. [PMID: 34815797 PMCID: PMC8581436 DOI: 10.7150/thno.63743] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Serum-derived exosomes are correlated with disease severity of human systemic lupus erythematosus (SLE). The proteins in the T-cell-derived exosomes from SLE patients could contribute to inflammation. Methods: We characterized proteins of T cell-derived exosomes from SLE patients and healthy controls by proteomics. To study the potential pathogenic role of the identified exosomal protein, we generated and characterized T-cell-specific transgenic mice that overexpressed the identified protein in T cells using immunohistochemistry, immunoblotting, and single-cell RNA sequencing. Results: We identified an overexpressed protein, bactericidal/permeability-increasing protein (BPI), in SLE T cells and T-cell-derived exosomes. T-cell-specific BPI transgenic (Lck-BPI Tg) mice showed multi-tissue inflammation with early induction of serum IL-1β levels, as well as serum triglyceride and creatinine levels. Interestingly, exosomes of Lck-BPI Tg T cells stimulated IL-1β expression of wild-type recipient macrophages. Remarkably, adoptive transfer of BPI-containing exosomes increased serum IL-1β and autoantibody levels in recipient mice. The transferred exosomes infiltrated into multiple tissues of recipient mice, resulting in hepatitis, nephritis, and arthritis. ScRNA-seq showed that Lck-BPI Tg T cells displayed a decrease of Treg population, which was concomitant with ZFP36L2 upregulation and Helios downregulation. Furthermore, in vitro Treg differentiation was reduced by BPI transgene and enhanced by BPI knockout. Conclusions: BPI is a negative regulator of Treg differentiation. BPI overexpression in T-cell-derived exosomes or peripheral blood T cells may be a biomarker and pathogenic factor for human SLE nephritis, hepatitis, and arthritis.
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Affiliation(s)
- Huai-Chia Chuang
- Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan
| | - Ming-Han Chen
- Division of Allergy, Immunology, and Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Ming Chen
- Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Huang-Yu Yang
- Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yi-Ru Ciou
- Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan
| | - Chia-Hsin Hsueh
- Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan
| | - Ching-Yi Tsai
- Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan
| | - Tse-Hua Tan
- Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA
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Bansal S, Limaye AP, Lee J, Fleming T, Poulson C, Omar A, Hachem R, Bharat A, Bremner RM, Smith MA, Mohanakumar T. Circulating exosomes induced by respiratory viral infections in lung transplant recipients activate cellular stress, innate immune pathways and epithelial to mesenchymal transition. Transpl Immunol 2021; 69:101480. [PMID: 34619318 DOI: 10.1016/j.trim.2021.101480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/01/2021] [Accepted: 10/02/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Chronic lung transplant rejection occurs in over 50% of lung transplant recipients and mechanism of chronic rejection is unknown. Evaluation of potential mechanism of exosomes from lung transplant recipients diagnosed with respiratory viral infection (RVI) in inducing chronic lung allograft dysfunction (CLAD). METHOD Exosomes were isolated from lung transplant recipients followed by DNA and RNA isolation from exosomes. Cell signaling mechanisms were studied by co-culturing exosomes with human epithelial cells. Mice were immunized with exosomes and lung homogenates were studied for immune signaling proteins. RESULTS Exosomes from lung transplant recipients with RVI carry nucleic acids which are capable of inducing innate immune signaling, endoplasmic reticulum stress, and epithelial mesenchymal transition. CONCLUSION Therefore, we propose that RVI can lead to induction of exosomes that initiate the process leading to CLAD in mice models. These novel findings identified the molecular mechanisms by which RVI increases the risk of CLAD.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ajit P Limaye
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, United States of America
| | - John Lee
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Christin Poulson
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ashraf Omar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ramsey Hachem
- Washington University School of Medicine, Department of Medicine, St. Louis, MO, United States of America
| | - Ankit Bharat
- Northwestern University, Chicago, Chicago, IL, United States of America
| | - Ross M Bremner
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Michael A Smith
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - T Mohanakumar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America.
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Sharma AK. The emerging role of exosomal cargo in allograft rejection after lung transplantation. J Heart Lung Transplant 2021; 41:34-36. [PMID: 34756654 DOI: 10.1016/j.healun.2021.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 10/20/2022] Open
Affiliation(s)
- Ashish K Sharma
- Departments of Surgery, Pulmonary & Critical Care Medicine, Physiology & Functional Genomics, and Pharmacology & Therapeutics, University of Florida, Gainesville, Florida.
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Gurunathan S, Kang MH, Kim JH. Diverse Effects of Exosomes on COVID-19: A Perspective of Progress From Transmission to Therapeutic Developments. Front Immunol 2021; 12:716407. [PMID: 34394121 PMCID: PMC8355618 DOI: 10.3389/fimmu.2021.716407] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/05/2021] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus and the causative agent of the current global pandemic of coronavirus disease 2019 (COVID-19). There are currently no FDA-approved antiviral drugs for COVID-19 and there is an urgent need to develop treatment strategies that can effectively suppress SARS-CoV-2 infection. Numerous approaches have been researched so far, with one of them being the emerging exosome-based therapies. Exosomes are nano-sized, lipid bilayer-enclosed structures, share structural similarities with viruses secreted from all types of cells, including those lining the respiratory tract. Importantly, the interplay between exosomes and viruses could be potentially exploited for antiviral drug and vaccine development. Exosomes are produced by virus-infected cells and play crucial roles in mediating communication between infected and uninfected cells. SARS-CoV-2 modulates the production and composition of exosomes, and can exploit exosome formation, secretion, and release pathways to promote infection, transmission, and intercellular spread. Exosomes have been exploited for therapeutic benefits in patients afflicted with various diseases including COVID-19. Furthermore, the administration of exosomes loaded with immunomodulatory cargo in combination with antiviral drugs represents a novel intervention for the treatment of diseases such as COVID-19. In particular, exosomes derived from mesenchymal stem cells (MSCs) are used as cell-free therapeutic agents. Mesenchymal stem cell derived exosomes reduces the cytokine storm and reverse the inhibition of host anti-viral defenses associated with COVID-19 and also enhances mitochondrial function repair lung injuries. We discuss the role of exosomes in relation to transmission, infection, diagnosis, treatment, therapeutics, drug delivery, and vaccines, and present some future perspectives regarding their use for combating COVID-19.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, South Korea
| | - Min Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, South Korea
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, South Korea
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50
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Yan YY, Zhou WM, Wang YQ, Guo QR, Zhao FX, Zhu ZY, Xing YX, Zhang HY, Aljofan M, Jarrahi AM, Makabel B, Zhang JY. The Potential Role of Extracellular Vesicles in COVID-19 Treatment: Opportunity and Challenge. Front Mol Biosci 2021; 8:699929. [PMID: 34368228 PMCID: PMC8345113 DOI: 10.3389/fmolb.2021.699929] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 07/08/2021] [Indexed: 12/13/2022] Open
Abstract
SARS-CoV-2 infection has become an urgent public health concern worldwide, severely affecting our society and economy due to the long incubation time and high prevalence. People spare no effort on the rapid development of vaccine and treatment all over the world. Amongst the numerous ways of tackling this pandemic, some approaches using extracellular vesicles (EVs) are emerging. In this review, we summarize current prevalence and pathogenesis of COVID-19, involving the combination of SARS-CoV-2 and virus receptor ACE2, endothelial dysfunction and micro thrombosis, together with cytokine storm. We also discuss the ongoing EVs-based strategies for the treatment of COVID-19, including mesenchymal stem cell (MSC)-EVs, drug-EVs, vaccine-EVs, platelet-EVs, and others. This manuscript provides the foundation for the development of targeted drugs and vaccines for SARS-CoV-2 infections.
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Affiliation(s)
- Yan-yan Yan
- School of Medicine, Shanxi Datong University, Datong, China
| | - Wen-min Zhou
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yu-qing Wang
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qiao-ru Guo
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Xinjiang Institute of Materia Medica, Urumqi, China
| | - Fu-xi Zhao
- School of Medicine, Shanxi Datong University, Datong, China
| | - Zhuang-yan Zhu
- School of Medicine, Shanxi Datong University, Datong, China
| | - Yan-xia Xing
- School of Medicine, Shanxi Datong University, Datong, China
| | - Hai-yan Zhang
- School of Medicine, Shanxi Datong University, Datong, China
| | - Mohamad Aljofan
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | | | | | - Jian-ye Zhang
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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