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Cambier S, Beretta F, Nooyens A, Metzemaekers M, Pörtner N, Kaes J, de Carvalho AC, Cortesi EE, Beeckmans H, Hooft C, Gouwy M, Struyf S, Marques RE, Ceulemans LJ, Wauters J, Vanaudenaerde BM, Vos R, Proost P. Heterogeneous neutrophils in lung transplantation and proteolytic CXCL8 activation in COVID-19, influenza and lung transplant patient lungs. Cell Mol Life Sci 2024; 81:475. [PMID: 39625496 PMCID: PMC11615237 DOI: 10.1007/s00018-024-05500-z] [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: 03/29/2024] [Revised: 09/20/2024] [Accepted: 10/31/2024] [Indexed: 12/06/2024]
Abstract
Elevated neutrophil counts in broncho-alveolar lavage (BAL) fluids of lung transplant (LTx) patients with chronic lung allograft dysfunction (CLAD) are associated with disease pathology. However, phenotypical characteristics of these cells remained largely unknown. Moreover, despite enhanced levels of the most potent human neutrophil-attracting chemokine CXCL8 in BAL fluid, no discrimination had been made between natural NH2-terminally truncated CXCL8 proteoforms, which exhibit up to 30-fold differences in biological activity. Therefore, we aimed to characterize the neutrophil maturation and activation state, as well as proteolytic activation of CXCL8, in BAL fluids and peripheral blood of LTx patients with CLAD or infection and stable LTx recipients. Flow cytometry and microscopy revealed a high diversity in neutrophil maturity in blood and BAL fluid, ranging from immature band to hypersegmented aged cells. In contrast, the activation phenotype of neutrophils in BAL fluid was remarkably homogeneous. The highly potentiated NH2-terminally truncated proteoforms CXCL8(6-77), CXCL8(8-77) and CXCL8(9-77), but also the partially inactivated CXCL8(10-77), were detected in BAL fluids of CLAD and infected LTx patients, as well as in COVID-19 and influenza patient cohorts by tandem mass spectrometry. Moreover, the most potent proteoform CXCL8(9-77) specifically correlated with the neutrophil counts in the LTx BAL fluids. Finally, rapid proteolysis of CXCL8 in BAL fluids could be inhibited by a combination of serine and metalloprotease inhibitors. In conclusion, proteolytic activation of CXCL8 promotes neutrophilic inflammation in LTx patients. Therefore, application of protease inhibitors may hold pharmacological promise for reducing excessive neutrophil-mediated inflammation and collateral tissue damage in the lungs.
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Affiliation(s)
- Seppe Cambier
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Fabio Beretta
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Amber Nooyens
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Mieke Metzemaekers
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Noëmie Pörtner
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Janne Kaes
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Ana Carolina de Carvalho
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
- Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Emanuela E Cortesi
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Hanne Beeckmans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Charlotte Hooft
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium
| | - Rafael E Marques
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
| | - Laurens J Ceulemans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Joost Wauters
- Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
- Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Bart M Vanaudenaerde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Robin Vos
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega - Herestraat 49, box 1042, Leuven, 3000, Belgium.
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Renaud-Picard B, Berra G, Hwang D, Huszti E, Miyamoto E, Berry GJ, Pal P, Juvet S, Keshavjee S, Martinu T. Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation. J Heart Lung Transplant 2024; 43:1701-1715. [PMID: 38663465 DOI: 10.1016/j.healun.2024.04.002] [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: 08/23/2023] [Revised: 03/11/2024] [Accepted: 04/09/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Long-term survival after lung transplantation (LTx) remains limited by chronic lung allograft dysfunction (CLAD), which includes 2 main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types. METHODS Peripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, and epithelial and vascular abnormalities. RESULTS CLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in histologic scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p = 0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes, and airway fibrosis. Immunofluorescence staining demonstrated a trend toward a lower frequency of club cells in CLAD and a higher frequency of apoptotic club cells in BOS samples (p = 0.01). CONCLUSIONS CLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathologic changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD histologic assessments.
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Affiliation(s)
- Benjamin Renaud-Picard
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; INSERM Unité Mixte de Recherche 1260, Regenerative Nanomedicine, University of Strasbourg, Strasbourg, France
| | - Gregory Berra
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Service de Pneumologie, Département de Médecine, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - David Hwang
- Department of Pathology, Sunnybrook Hospital, Toronto, Ontario, Canada
| | - Ella Huszti
- Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada
| | - Ei Miyamoto
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Gerald J Berry
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Prodipto Pal
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
| | - Stephen Juvet
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Shaf Keshavjee
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Tereza Martinu
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Toronto Lung Transplant Program, Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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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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Kaes J, Pollenus E, Hooft C, Liu H, Aelbrecht C, Cambier S, Jin X, Van Slambrouck J, Beeckmans H, Kerckhof P, Velde GV, Van Raemdonck D, Yildirim AÖ, Van den Steen PE, Vos R, Ceulemans LJ, Vanaudenaerde BM. The Immunopathology of Pulmonary Rejection after Murine Lung Transplantation. Cells 2024; 13:241. [PMID: 38334633 PMCID: PMC10854916 DOI: 10.3390/cells13030241] [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: 12/27/2023] [Revised: 01/21/2024] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
To improve outcomes following lung transplantation, it is essential to understand the immunological mechanisms that result in chronic graft failure. The associated clinical syndrome is termed chronic lung allograft dysfunction (CLAD), which is known to be induced by alloimmune-dependent (i.e., rejection) and alloimmune-independent factors (e.g., infections, reflux and environmental factors). We aimed to explore the alloimmune-related mechanism, i.e., pulmonary rejection. In this study, we use a murine orthotopic left lung transplant model using isografts and allografts (C57BL/6 or BALB/c as donors to C57BL/6 recipients), with daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone). Serial sacrifice was performed at days 1, 7 and 35 post-transplantation (n = 6 at each time point for each group). Left transplanted lungs were harvested, a single-cell suspension was made and absolute numbers of immune cells were quantified using multicolor flow cytometry. The rejection process followed the principles of a classic immune response, including innate but mainly adaptive immune cells. At day 7 following transplantation, the numbers of interstitial macrophages, monocytes, dendritic cells, NK cells, NKT cells, CD4+ T cells and CD8+ T and B cells were increased in allografts compared with isografts. Only dendritic cells and CD4+ T cells remained elevated at day 35 in allografts. Our study provides insights into the immunological mechanisms of true pulmonary rejection after murine lung transplantation. These results might be important in further research on diagnostic evaluation and treatment for CLAD.
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Affiliation(s)
- Janne Kaes
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Emilie Pollenus
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; (E.P.)
| | - Charlotte Hooft
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Hengshuo Liu
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Munich, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany (A.Ö.Y.)
| | - Celine Aelbrecht
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Seppe Cambier
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium;
| | - Xin Jin
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Jan Van Slambrouck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Hanne Beeckmans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Pieterjan Kerckhof
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
| | - Greetje Vande Velde
- Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium
| | - Dirk Van Raemdonck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Ali Önder Yildirim
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Munich, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany (A.Ö.Y.)
| | - Philippe E. Van den Steen
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; (E.P.)
| | - Robin Vos
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
- Department of Respiratory Diseases, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Laurens J. Ceulemans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
- Department of Thoracic Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Bart M. Vanaudenaerde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium; (J.K.)
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Li X, Wu J, Zhu S, Wei Q, Wang L, Chen J. Intragraft immune cells: accomplices or antagonists of recipient-derived macrophages in allograft fibrosis? Cell Mol Life Sci 2023; 80:195. [PMID: 37395809 DOI: 10.1007/s00018-023-04846-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/22/2023] [Accepted: 06/21/2023] [Indexed: 07/04/2023]
Abstract
Organ fibrosis caused by chronic allograft rejection is a major concern in the field of transplantation. Macrophage-to-myofibroblast transition plays a critical role in chronic allograft fibrosis. Adaptive immune cells (such as B and CD4+ T cells) and innate immune cells (such as neutrophils and innate lymphoid cells) participate in the occurrence of recipient-derived macrophages transformed to myofibroblasts by secreting cytokines, which eventually leads to fibrosis of the transplanted organ. This review provides an update on the latest progress in understanding the plasticity of recipient-derived macrophages in chronic allograft rejection. We discuss here the immune mechanisms of allograft fibrosis and review the reaction of immune cells in allograft. The interactions between immune cells and the process of myofibroblast formulation are being considered for the potential therapeutic targets of chronic allograft fibrosis. Therefore, research on this topic seems to provide novel clues for developing strategies for preventing and treating allograft fibrosis.
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Affiliation(s)
- Xiaoping Li
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
- Department of Pediatrics, First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jing Wu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Shan Zhu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Qiuyu Wei
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Liyan Wang
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Jingtao Chen
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China.
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China.
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Markers of Bronchiolitis Obliterans Syndrome after Lung Transplant: Between Old Knowledge and Future Perspective. Biomedicines 2022; 10:biomedicines10123277. [PMID: 36552035 PMCID: PMC9775233 DOI: 10.3390/biomedicines10123277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Bronchiolitis obliterans syndrome (BOS) is the most common form of CLAD and is characterized by airflow limitation and an obstructive spirometric pattern without high-resolution computed tomography (HRCT) evidence of parenchymal opacities. Computed tomography and microCT analysis show abundant small airway obstruction, starting from the fifth generation of airway branching and affecting up to 40-70% of airways. The pathogenesis of BOS remains unclear. It is a multifactorial syndrome that leads to pathological tissue changes and clinical manifestations. Because BOS is associated with the worst long-term survival in LTx patients, many studies are focused on the early identification of BOS. Markers may be useful for diagnosis and for understanding the molecular and immunological mechanisms involved in the onset of BOS. Diagnostic and predictive markers of BOS have also been investigated in various biological materials, such as blood, BAL, lung tissue and extracellular vesicles. The aim of this review was to evaluate the scientific literature on markers of BOS after lung transplant. We performed a systematic review to find all available data on potential prognostic and diagnostic markers of BOS.
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Lynch TJ, Ahlers BA, Swatek AM, Ievlev V, Pai AC, Brooks L, Tang Y, Evans IA, Meyerholz DK, Engelhardt JF, Parekh KR. Ferret Lung Transplantation Models Differential Lymphoid Aggregate Morphology Between Restrictive and Obstructive Forms of Chronic Lung Allograft Dysfunction. Transplantation 2022; 106:1974-1989. [PMID: 35442232 PMCID: PMC9529760 DOI: 10.1097/tp.0000000000004148] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Long-term survival after lung transplantation remains limited by chronic lung allograft dysfunction (CLAD). CLAD has 2 histologic phenotypes, namely obliterative bronchiolitis (OB) and restrictive alveolar fibroelastosis (AFE), which have distinct clinical presentations, pathologies, and outcomes. Understanding of OB versus AFE pathogenesis would improve with better animal models. METHODS We utilized a ferret orthotopic single-lung transplantation model to characterize allograft fibrosis as a histologic measure of CLAD. Native lobes and "No CLAD" allografts lacking aberrant histology were used as controls. We used morphometric analysis to evaluate the size and abundance of B-cell aggregates and tertiary lymphoid organs (TLOs) and their cell composition. Quantitative RNA expression of 47 target genes was performed simultaneously using a custom QuantiGene Plex Assay. RESULTS Ferret lung allografts develop the full spectrum of human CLAD histology including OB and AFE subtypes. While both OB and AFE allografts developed TLOs, TLO size and number were greater with AFE histology. More activated germinal center cells marked by B-cell lymphoma 6 Transcription Repressor, (B-cell lymphoma 6) expression and fewer cells expressing forkhead box P3 correlated with AFE, congruent with greater diffuse immunoglobulin, plasma cell abundance, and complement 4d staining. Furthermore, forkhead box P3 RNA induction was significant in OB allografts specifically. RNA expression changes were seen in native lobes of animals with AFE but not OB when compared with No CLAD native lobes. CONCLUSIONS The orthotopic ferret single-lung transplant model provides unique opportunities to better understand factors that dispose allografts to OB versus AFE. This will help develop potential immunomodulatory therapies and antifibrotic approaches for lung transplant patients.
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Affiliation(s)
- Thomas J. Lynch
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Bethany A. Ahlers
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Anthony M. Swatek
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Vitaly Ievlev
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Albert C. Pai
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Leonard Brooks
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Yinghua Tang
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Idil A. Evans
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - David K. Meyerholz
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - John F. Engelhardt
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Kalpaj R. Parekh
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
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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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Pulmonary graft-versus-host disease and chronic lung allograft dysfunction: two sides of the same coin? THE LANCET RESPIRATORY MEDICINE 2022; 10:796-810. [DOI: 10.1016/s2213-2600(22)00001-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/17/2021] [Accepted: 01/04/2022] [Indexed: 11/23/2022]
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10
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Ohm B, Jungraithmayr W. B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications. Front Immunol 2022; 13:845867. [PMID: 35320934 PMCID: PMC8934882 DOI: 10.3389/fimmu.2022.845867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Allograft rejection remains the major hurdle in lung transplantation despite modern immunosuppressive treatment. As part of the alloreactive process, B cells are increasingly recognized as modulators of alloimmunity and initiators of a donor-specific humoral response. In chronically rejected lung allografts, B cells contribute to the formation of tertiary lymphoid structures and promote local alloimmune responses. However, B cells are functionally heterogeneous and some B cell subsets may promote alloimmune tolerance. In this review, we describe the current understanding of B-cell-dependent mechanisms in pulmonary allograft rejection and highlight promising future strategies that employ B cell-targeted therapies.
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Affiliation(s)
- Birte Ohm
- Department of Thoracic Surgery, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
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11
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Ram S, Verleden SE, Bell AJ, Hoff BA, Labaki WW, Murray S, Vanaudenaerde BM, Vos R, Verleden GM, Kazerooni EA, Galbán S, Hatt CR, Han MK, Lama VN, Galbán CJ. Quantitative CT Correlates with Local Inflammation in Lung of Patients with Subtypes of Chronic Lung Allograft Dysfunction. Cells 2022; 11:699. [PMID: 35203345 PMCID: PMC8870691 DOI: 10.3390/cells11040699] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/08/2022] [Accepted: 02/11/2022] [Indexed: 02/03/2023] Open
Abstract
Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6). Topological metrics were determined from each PRM classification and compared to structural and biological markers determined from microCT and histopathology of lung core samples. Whole-lung measurements of PRM-defined functional small airways disease (fSAD), which serves as a readout of BOS, were significantly elevated in BOS versus RAS patients (p = 0.01). At the core-level, PRM-defined parenchymal disease, a potential readout of RAS, was found to correlate to neutrophil and collagen I levels (p < 0.05). We demonstrate the relationship of structural and biological markers to the CT-based distribution and arrangement of PRM-derived readouts of BOS and RAS.
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Affiliation(s)
- Sundaresh Ram
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (A.J.B.); (B.A.H.); (E.A.K.); (S.G.)
| | - Stijn E. Verleden
- Antwerp Surgical Training, Anatomy and Research Centre (ASTARC), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, 2610 Antwerp, Belgium;
- Department of Chronic Diseases and Metabolism (CHROMETA), Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (B.M.V.); (R.V.); (G.M.V.)
| | - Alexander J. Bell
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (A.J.B.); (B.A.H.); (E.A.K.); (S.G.)
| | - Benjamin A. Hoff
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (A.J.B.); (B.A.H.); (E.A.K.); (S.G.)
| | - Wassim W. Labaki
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (W.W.L.); (M.K.H.); (V.N.L.)
| | - Susan Murray
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Bart M. Vanaudenaerde
- Department of Chronic Diseases and Metabolism (CHROMETA), Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (B.M.V.); (R.V.); (G.M.V.)
| | - Robin Vos
- Department of Chronic Diseases and Metabolism (CHROMETA), Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (B.M.V.); (R.V.); (G.M.V.)
- Respiratory Division, University Hospital Leuven, 3000 Leuven, Belgium
| | - Geert M. Verleden
- Department of Chronic Diseases and Metabolism (CHROMETA), Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (B.M.V.); (R.V.); (G.M.V.)
- Respiratory Division, University Hospital Leuven, 3000 Leuven, Belgium
| | - Ella A. Kazerooni
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (A.J.B.); (B.A.H.); (E.A.K.); (S.G.)
| | - Stefanie Galbán
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (A.J.B.); (B.A.H.); (E.A.K.); (S.G.)
| | | | - Meilan K. Han
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (W.W.L.); (M.K.H.); (V.N.L.)
| | - Vibha N. Lama
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (W.W.L.); (M.K.H.); (V.N.L.)
| | - Craig J. Galbán
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.); (A.J.B.); (B.A.H.); (E.A.K.); (S.G.)
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12
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Bos S, Filby AJ, Vos R, Fisher AJ. Effector immune cells in Chronic Lung Allograft Dysfunction: a Systematic Review. Immunology 2022; 166:17-37. [PMID: 35137398 PMCID: PMC9426626 DOI: 10.1111/imm.13458] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/13/2022] [Accepted: 02/02/2022] [Indexed: 11/29/2022] Open
Abstract
Chronic lung allograft dysfunction (CLAD) remains the major barrier to long‐term survival after lung transplantation and improved insight into its underlying immunological mechanisms is critical to better understand the disease and to identify treatment targets. We systematically searched the electronic databases of PubMed and EMBASE for original research publications, published between January 2000 and April 2021, to comprehensively assess current evidence on effector immune cells in lung tissue and bronchoalveolar lavage fluid from lung transplant recipients with CLAD. Literature search revealed 1351 articles, 76 of which met the criteria for inclusion in our analysis. Our results illustrate significant complexity in both innate and adaptive immune cell responses in CLAD, along with presence of numerous immune cell products, including cytokines, chemokines and proteases associated with tissue remodelling. A clear link between neutrophils and eosinophils and CLAD incidence has been seen, in which eosinophils more specifically predisposed to restrictive allograft syndrome. The presence of cytotoxic and T‐helper cells in CLAD pathogenesis is well‐documented, although it is challenging to draw conclusions about their role in tissue processes from predominantly bronchoalveolar lavage data. In restrictive allograft syndrome, a more prominent humoral immune involvement with increased B cells, immunoglobulins and complement deposition is seen. Our evaluation of published studies over the last 20 years summarizes the complex multifactorial immunopathology of CLAD onset and progression. It highlights the phenotype of several key effector immune cells involved in CLAD pathogenesis, as well as the paucity of single cell resolution spatial studies in lung tissue from patients with CLAD.
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Affiliation(s)
- Saskia Bos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom.,Institute of Transplantation, The Newcastle Upon Tyne Hospital NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
| | - Andrew J Filby
- Flow Cytometry Core and Innovation, Methodology and Application Research Theme, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Robin Vos
- Department 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, United Kingdom.,Institute of Transplantation, The Newcastle Upon Tyne Hospital NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
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13
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Pabst R. The bronchus-associated-lymphoid tissue (BALT) an unique lymphoid organ in man and animals. Ann Anat 2021; 240:151833. [PMID: 34670121 DOI: 10.1016/j.aanat.2021.151833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/27/2021] [Accepted: 08/29/2021] [Indexed: 01/10/2023]
Abstract
The development structure and number of bronchus-associated lymphoid tissue (BALT) will be described in many different animals (like chicken, rabbit, mouse, rat, farm animals and particular the pig, monkey) and these data compared to healthy man and in human diseases. The term induced BALT should not be used because it is a tertiary lymphoid structure, which lacks the contact to a bronchus and does not consist of the important area (dome area) which is essential for antigen uptake of microbial stimuli, which are essential in the development of BALT. Mycoplasma seems to play a critical role as shown in pigs but there not been documented in other species like rabbits. More studies have to be performed in health and disease (e.g. in apes) to document the structural and functional basis to use BALT as an entry site for vaccination protocols.
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Affiliation(s)
- Reinhard Pabst
- Immunomorphology, Centre of Anatomy, Medical School Hannover, Germany.
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14
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Müller C, Rosmark O, Åhrman E, Brunnström H, Wassilew K, Nybom A, Michaliková B, Larsson H, Eriksson LT, Schultz HH, Perch M, Malmström J, Wigén J, Iversen M, Westergren-Thorsson G. Protein Signatures of Remodeled Airways in Transplanted Lungs with Bronchiolitis Obliterans Syndrome Obtained Using Laser-Capture Microdissection. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1398-1411. [PMID: 34111430 DOI: 10.1016/j.ajpath.2021.05.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 04/28/2021] [Accepted: 05/12/2021] [Indexed: 10/25/2022]
Abstract
Bronchiolitis obliterans syndrome, a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histologic correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, which ultimately lead to organ failure. The molecular composition of these lesions is unknown. In this sutdy, the protein composition of the lesions in explanted lungs from four end-stage bronchiolitis obliterans syndrome patients was analyzed using laser-capture microdissection and optimized sample preparation protocols for mass spectrometry. Immunohistochemistry and immunofluorescence were used to determine the spatial distribution of commonly identified proteins on the tissue level, and protein signatures for 14 obliterative bronchiolitis lesions were established. A set of 39 proteins, identified in >75% of lesions, included distinct structural proteins (collagen types IV and VI) and cellular components (actins, vimentin, and tryptase). Each respective lesion exhibited a unique composition of proteins (on average, n = 66 proteins), thereby mirroring the morphologic variation of the lesions. Antibody-based staining confirmed these mass spectrometry-based findings. The 14 analyzed obliterative bronchiolitis lesions showed variations in their protein content, but also common features. This study provides molecular and morphologic insights into the development of chronic rejection after lung transplantation. The protein patterns in the lesions were correlated to pathways of extracellular matrix organization, tissue development, and wound healing processes.
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Affiliation(s)
- Catharina Müller
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Oskar Rosmark
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Emma Åhrman
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; Division of Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Hans Brunnström
- Division of Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Division of Laboratory Medicine, Department of Genetics and Pathology, Region Skåne, Lund, Sweden
| | - Katharina Wassilew
- Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Annika Nybom
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Barbora Michaliková
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Hillevi Larsson
- Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, Sweden
| | - Leif T Eriksson
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, Sweden
| | - Hans H Schultz
- Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Michael Perch
- Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Johan Malmström
- Division of Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Jenny Wigén
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Martin Iversen
- Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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15
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Nemska S, Daubeuf F, Obrecht A, Israel-Biet D, Stern M, Kessler R, Roux A, Tavakoli R, Villa P, Tissot A, Danger R, Reber L, Durand E, Foureau A, Brouard S, Magnan A, Frossard N. Overexpression of the MSK1 Kinase in Patients With Chronic Lung Allograft Dysfunction and Its Confirmed Role in a Murine Model. Transplantation 2021; 105:1212-1224. [PMID: 33560725 DOI: 10.1097/tp.0000000000003606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Chronic lung allograft dysfunction (CLAD) and its obstructive form, the obliterative bronchiolitis (OB), are the main long-term complications related to high mortality rate postlung transplantation. CLAD treatment lacks a significant success in survival. Here, we investigated a new strategy through inhibition of the proinflammatory mitogen- and stress-activated kinase 1 (MSK1) kinase. METHODS MSK1 expression was assessed in a mouse OB model after heterotopic tracheal allotransplantation. Pharmacological inhibition of MSK1 (H89, fasudil, PHA767491) was evaluated in the murine model and in a translational model using human lung primary fibroblasts in proinflammatory conditions. MSK1 expression was graded over time in biopsies from a cohort of CLAD patients. RESULTS MSK1 mRNA progressively increased during OB (6.4-fold at D21 posttransplantation). Inhibition of MSK1 allowed to counteract the damage to the epithelium (56% restoration for H89), and abolished the recruitment of MHCII+ (94%) and T cells (100%) at the early inflammatory phase of OB. In addition, it markedly decreased the late fibroproliferative obstruction in allografts (48%). MSK1 inhibitors decreased production of IL-6 (whose transcription is under the control of MSK1) released from human lung fibroblasts (96%). Finally, we confirmed occurrence of a 2.9-fold increased MSK1 mRNA expression in lung biopsies in patients at 6 months before CLAD diagnosis as compared to recipients with stable lung function. CONCLUSIONS These findings suggest the overall interest of the MSK1 kinase either as a marker or as a potential therapeutic target in lung dysfunction posttransplantation.
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Affiliation(s)
- Simona Nemska
- Laboratoire d'Innovation Thérapeutique UMR 7200, LabEx Medalis, CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
- Institute of Veterinary Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - François Daubeuf
- Laboratoire d'Innovation Thérapeutique UMR 7200, LabEx Medalis, CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
- Plateforme de Chimie Biologie Intégrative de Strasbourg (PCBIS) UMS 3286 CNRS, Université de Strasbourg, Labex Medalis, 300 Bld Brant, Illkirch, France
| | - Adeline Obrecht
- Plateforme de Chimie Biologie Intégrative de Strasbourg (PCBIS) UMS 3286 CNRS, Université de Strasbourg, Labex Medalis, 300 Bld Brant, Illkirch, France
| | | | - Marc Stern
- Hôpital Foch, Suresnes, INRAe UMR 0892, Université de Versailles Saint-Quentin Paris-Saclay, Paris, France
| | - Romain Kessler
- Service de Pneumologie, CHU Strasbourg, Strasbourg, France
| | - Antoine Roux
- Hôpital Foch, Suresnes, INRAe UMR 0892, Université de Versailles Saint-Quentin Paris-Saclay, Paris, France
| | - Reza Tavakoli
- Institute of Veterinary Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
| | - Pascal Villa
- Plateforme de Chimie Biologie Intégrative de Strasbourg (PCBIS) UMS 3286 CNRS, Université de Strasbourg, Labex Medalis, 300 Bld Brant, Illkirch, France
| | - Adrien Tissot
- CHU Nantes, Inserm, UMR 1064, Centre de Recherche en Transplantation et Immunologie, Nantes Université, ITUN, Nantes, France
- Service de Pneumologie, L'institut du thorax, CHU Nantes, Nantes, France
| | - Richard Danger
- CHU Nantes, Inserm, UMR 1064, Centre de Recherche en Transplantation et Immunologie, Nantes Université, ITUN, Nantes, France
- Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Labex IGO, Nantes, France
| | - Laurent Reber
- Laboratoire d'Innovation Thérapeutique UMR 7200, LabEx Medalis, CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
| | - Eugénie Durand
- CHU Nantes, Inserm, UMR 1064, Centre de Recherche en Transplantation et Immunologie, Nantes Université, ITUN, Nantes, France
| | - Aurore Foureau
- CHU Nantes, Inserm, UMR 1064, Centre de Recherche en Transplantation et Immunologie, Nantes Université, ITUN, Nantes, France
- Service de Pneumologie, L'institut du thorax, CHU Nantes, Nantes, France
| | - Sophie Brouard
- CHU Nantes, Inserm, UMR 1064, Centre de Recherche en Transplantation et Immunologie, Nantes Université, ITUN, Nantes, France
- Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Labex IGO, Nantes, France
| | - Antoine Magnan
- Service de Pneumologie, L'institut du thorax, CHU Nantes, Nantes, France
| | - Nelly Frossard
- Laboratoire d'Innovation Thérapeutique UMR 7200, LabEx Medalis, CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
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16
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Klouda T, Vargas SO, Midyat L. Restrictive allograft syndrome after lung transplantation. Pediatr Transplant 2021; 25:e14000. [PMID: 33728767 DOI: 10.1111/petr.14000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/07/2021] [Accepted: 02/22/2021] [Indexed: 11/29/2022]
Abstract
Despite recent advances over the past decade in lung transplantation including improved surgical technique and immunotherapy, the diagnosis and treatment of chronic lung allograft dysfunction remains a significant barrier to recipient survival. Aside from bronchiolitis obliterans syndrome, a restrictive phenotype called restrictive allograft syndrome has recently been recognized and affects up to 35% of all patients with CLAD. The main characteristics of RAS include a persistent and unexplained decline in lung function compared to baseline and persistent parenchymal infiltrates on imaging. The median survival after diagnosis of RAS is 6 to 18 months, significantly shorter than other forms of CLAD. Treatment options are limited, as therapies used for BOS are typically ineffective at halting disease progression. Specific medications such as fibrinolytics are lacking large, multicenter prospective studies. In this manuscript, we discuss the definition, mechanism, and characteristics of RAS while highlighting the similarities and differences between other forms of CLAD. We also review the diagnoses along with current and potential treatment options that are available for patients. Finally, we discuss the existing knowledge gaps and areas for future research to improve patient outcomes and understanding of RAS.
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Affiliation(s)
- Timothy Klouda
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sara O Vargas
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Levent Midyat
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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17
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Pezzuto F, Lunardi F, Vadori M, Zampieri D, Casiraghi F, Azzollini N, Vuljan SE, Mammana M, Vedovelli L, Schiavon M, Gregori D, Cozzi E, Rea F, Calabrese F. Chronic lung allograft pathology lesions in two rat strain combinations. J Thorac Dis 2021; 13:2833-2843. [PMID: 34164175 PMCID: PMC8182524 DOI: 10.21037/jtd-20-3415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Background Chronic lung allograft dysfunction remains an obstacle to long-term survival after lung transplantation. Two phenotypes have been described: obliterative bronchiolitis and restrictive allograft syndrome. Preclinical models are essential to analyze chronic lung allograft dysfunction pathophysiology. Methods Orthotopic lung transplants from 38 Lewis into Fischer 344 (Lew→F344) and 67 Brown-Norway into Lewis (BN→Lew) rats were performed in our center in the last decade. We carefully reviewed and quantified all grafts with chronic rejection (40 cases) (18 Lew→F344, 22 BN→Lew) with the aim to investigate if histological changes of chronic lung allograft dysfunction could be also detected in rat grafts. Results All animals showed human reminiscent histological lesions. Early chronic rejection lesions were detected in BN→Lew. End-stage chronic rejection with features of obliterative bronchiolitis was observed in 33% of Lew→F344; end-stage with restrictive allograft syndrome chronic rejection in 67% and 80% of Lew→F344 and BN→Lew, respectively. BN→Lew showed higher grades of endotheliitis, vascular fibrosis, and lower grades of lymphoid aggregates than Lew→F344 (P=0.007, P=0.043, P=0.004, respectively). Conclusions Chronic rejection lesions in rat lung allografts mimic those in humans. The frequent occurrence of restrictive allograft syndrome-like lesions in BN→Lew may be related to a higher degree of mismatch in this strain combination. These animal models could allow future mechanistic studies to better understand chronic lung allograft dysfunction pathogenesis.
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Affiliation(s)
- Federica Pezzuto
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Francesca Lunardi
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | | | - Davide Zampieri
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | | | - Nadia Azzollini
- Mario Negri Institute for Pharmacological Research, Bergamo, Italy
| | - Stefania Edith Vuljan
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Marco Mammana
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Luca Vedovelli
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Marco Schiavon
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Dario Gregori
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Emanuele Cozzi
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Federico Rea
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italy
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18
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Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction. Sci Rep 2021; 11:6799. [PMID: 33762606 PMCID: PMC7990920 DOI: 10.1038/s41598-021-85949-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/03/2021] [Indexed: 02/01/2023] Open
Abstract
Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.
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19
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Misumi K, Wheeler DS, Aoki Y, Combs MP, Braeuer RR, Higashikubo R, Li W, Kreisel D, Vittal R, Myers J, Lagstein A, Walker NM, Farver CF, Lama VN. Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction. JCI Insight 2020; 5:136533. [PMID: 33268593 PMCID: PMC7714414 DOI: 10.1172/jci.insight.136533] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 10/21/2020] [Indexed: 01/01/2023] Open
Abstract
Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into μMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory μ-chain (μs) double-KO (AID-/-μs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.
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Affiliation(s)
- Keizo Misumi
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - David S. Wheeler
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yoshiro Aoki
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael P. Combs
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Russell R. Braeuer
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Ryuji Higashikubo
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Wenjun Li
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Daniel Kreisel
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Ragini Vittal
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeffrey Myers
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Amir Lagstein
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Natalie M. Walker
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Carol F. Farver
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Vibha N. Lama
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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20
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Kaes J, Van der Borght E, Vanstapel A, Van Herck A, Sacreas A, Heigl T, Vanaudenaerde BM, Godinas L, Van Raemdonck DE, Ceulemans LJ, Neyrinck AP, Vos R, Verleden GM, Verleden SE. Peripheral Blood Eosinophilia Is Associated with Poor Outcome Post-Lung Transplantation. Cells 2020; 9:E2516. [PMID: 33233857 PMCID: PMC7699939 DOI: 10.3390/cells9112516] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/13/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022] Open
Abstract
Eosinophils play a role in many chronic lung diseases. In lung transplantation (LTx), increased eosinophils in bronchoalveolar lavage (BAL) was associated with worse outcomes. However, the effect of peripheral blood eosinophilia after LTx has not been investigated thoroughly. A retrospective study was performed including all LTx patients between 2011-2016. Chronic lung allograft dysfunction (CLAD)-free and graft survival were compared between patients with high and low blood eosinophils using an 8% threshold ever during follow-up. A total of 102 patients (27.1%) had high blood eosinophils (≥8%) (45 before CLAD and 17 after, 40 had no CLAD) and 274 (72.9%) had low eosinophils (<8%). Patients with high blood eosinophils demonstrated worse graft survival (p = 0.0001) and CLAD-free survival (p = 0.003) compared to low eosinophils. Patients with both high blood and high BAL (≥2%) eosinophils ever during follow-up had the worst outcomes. Within the high blood eosinophil group, 23.5% had RAS compared to 3% in the group with low eosinophils (p < 0.0001). After multivariate analysis, the association between high blood eosinophils and graft and CLAD-free survival remained significant (p = 0.036, p = 0.013) independent of high BAL eosinophils and infection at peak blood eosinophilia, among others. LTx recipients with ever ≥8% blood eosinophils demonstrate inferior graft and CLAD-free survival, specifically RAS, which requires further prospective research.
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Affiliation(s)
- Janne Kaes
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
| | - Elise Van der Borght
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
| | - Arno Vanstapel
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
- Department of Pathology, UH Leuven, B-3000 Leuven, Belgium
| | - Anke Van Herck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
- Department of Respiratory Diseases, Lung Transplant Unit, UH Leuven, B-3000 Leuven, Belgium;
| | - Annelore Sacreas
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
| | - Tobias Heigl
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
| | - Bart M. Vanaudenaerde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
| | - Laurent Godinas
- Department of Respiratory Diseases, Lung Transplant Unit, UH Leuven, B-3000 Leuven, Belgium;
| | - Dirk E. Van Raemdonck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
- Department of Thoracic Surgery, UH Leuven, B-3000 Leuven, Belgium
| | - Laurens J. Ceulemans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
- Department of Thoracic Surgery, UH Leuven, B-3000 Leuven, Belgium
| | - Arne P. Neyrinck
- Laboratory of Anesthesiology and Algology, Department of Cardiovascular Sciences, KU Leuven, B-3000 Leuven, Belgium;
| | - Robin Vos
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
- Department of Respiratory Diseases, Lung Transplant Unit, UH Leuven, B-3000 Leuven, Belgium;
| | - Geert M. Verleden
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
- Department of Respiratory Diseases, Lung Transplant Unit, UH Leuven, B-3000 Leuven, Belgium;
| | - Stijn E. Verleden
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, B-3000 Leuven, Belgium; (J.K.); (E.V.d.B.); (A.V.); (A.V.H.); (A.S.); (T.H.); (B.M.V.); (D.E.V.R.); (L.J.C.); (R.V.); (G.M.V.)
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21
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Darley DR, Ma J, Huszti E, Fiset P, Levy L, Hwang DM, Pal P, Klement W, Zamel R, Keshavjee S, Tomlinson G, Singer LG, Tikkanen JM, Martinu T. Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft dysfunction and reduced survival after lung transplantation - a retrospective single-center cohort study. Transpl Int 2020; 34:62-75. [PMID: 33025592 DOI: 10.1111/tri.13760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/06/2020] [Accepted: 09/28/2020] [Indexed: 01/14/2023]
Abstract
Long-term outcomes after lung transplantation remain inferior to those of other solid organ groups. The significance of eosinophils detected on transbronchial biopsies (TBBx) after lung transplantation and their relationship to long-term outcomes remain unknown. A retrospective single-center cohort study was performed of patients transplanted between January 01, 2001, and July 31, 2018, who had at least 1 TBBx with evaluable parenchymal tissue. Multivariable Cox proportional hazard models were used to assess the associations between eosinophil detection and: all-cause mortality and Chronic Lung Allograft Dysfunction (CLAD). 8887 TBBx reports from 1440 patients were reviewed for the mention of eosinophils in the pathology report. 112 (7.8%) patients were identified with eosinophils on at least one TBBx. The median (95% CI) survival time for all patients was 8.28 (7.32-9.31) years. Multivariable analysis, adjusted for clinical variables known to affect post-transplant outcomes, showed that the detection of eosinophils was independently associated with an increased risk of death (HR 1.51, 95% CI 1.24-1.85, p < 0.01) and CLAD (HR 1.35, 95% CI 1.07-1.70, P = 0.01). Eosinophils detected in TBBx are associated with an increased risk of CLAD and death. There may be benefit in specifically reporting the presence of eosinophils in TBBx reports and incorporating their presence in clinical decision-making.
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Affiliation(s)
- David R Darley
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada.,UNSW Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Jin Ma
- Biostatistics Research Unit, University Health Network, Toronto, ON, Canada
| | - Ella Huszti
- Biostatistics Research Unit, University Health Network, Toronto, ON, Canada
| | - Pierre Fiset
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | | | - David M Hwang
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada.,Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Prodipto Pal
- Department of Laboratory Medicine & Pathobiology, University Health Network, Toronto, ON, Canada
| | - William Klement
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Ricardo Zamel
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Shaf Keshavjee
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - George Tomlinson
- Biostatistics Research Unit, University Health Network, Toronto, ON, Canada
| | - Lianne G Singer
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Jussi M Tikkanen
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Tereza Martinu
- Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada
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22
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Verleden GM. The role of tissue eosinophils after lung transplantation: back into business? Transpl Int 2020; 34:59-61. [PMID: 33070387 DOI: 10.1111/tri.13774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 10/14/2020] [Indexed: 11/26/2022]
Affiliation(s)
- Geert M Verleden
- Department Repir Dis and Lung Transplantation Unit, University Hospital Gasthuisberg, Leuven, Belgium
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23
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LPS-induced Airway-centered Inflammation Leading to BOS-like Airway Remodeling Distinct From RAS-like Fibrosis in Rat Lung Transplantation. Transplantation 2020; 104:1150-1158. [PMID: 31929420 DOI: 10.1097/tp.0000000000003097] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Localization of inflammatory stimuli may direct lung allografts to different phenotypes of chronic dysfunction, such as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). We hypothesized that airway stimulation with lipopolysaccharide (LPS) in rats leads to airway-centered inflammation similar to human BOS. METHODS Rat left lung transplantation was conducted (donor: Brown Norway, recipient: Lewis). Allotransplant recipients received cyclosporine A (CsA) until postoperative day 56 with airway instillation of LPS (Allo-LPS, n = 8), phosphate buffered saline (Allo-PBS, n = 5) from days 35 to 46 (3 times a wk), or no further treatment (n = 4). Some allotransplant recipients received CsA until day 14 and were immunosuppression free after day 15 until day 56. Bronchial and pleural fibrosis were semiquantified; alveolar fibrosis was evaluated with a histological scale. RESULTS The Allo-LPS group had significantly increased International Society for Heart and Lung Transplantation rejection grades (grade A, P = 0.005; grade B, P = 0.004), bronchial obstructive proportion (0.34 ± 0.04% [Allo-LPS] versus 0.11 ± 0.04% [Allo-PBS], P = 0.006), and airway resistance (3.05 ± 1.78 cm H2O·s/mL [Allo-LPS] versus 0.83 ± 0.58 cm H2O·s/mL [Allo-PBS], P = 0.007) compared with other groups. Allotransplant recipients that underwent a short course of CsA developed RAS-like fibrosis involving the airways, alveoli, and pleura. CONCLUSIONS Airway instillation of LPS in allografts under immunosuppression resulted in BOS-like airway-centered inflammation and fibrosis distinct from RAS-like diffuse fibrosis, which was induced by a shortened course of immunosuppression. We propose novel animal models for BOS and RAS after lung transplantation.
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24
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Verleden SE, Von der Thüsen J, Roux A, Brouwers ES, Braubach P, Kuehnel M, Laenger F, Jonigk D. When tissue is the issue: A histological review of chronic lung allograft dysfunction. Am J Transplant 2020; 20:2644-2651. [PMID: 32185874 DOI: 10.1111/ajt.15864] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/03/2020] [Accepted: 03/05/2020] [Indexed: 01/25/2023]
Abstract
Although chronic lung allograft dysfunction (CLAD) remains the major life-limiting factor following lung transplantation, much of its pathophysiology remains unknown. The discovery that CLAD can manifest both clinically and morphologically in vastly different ways led to the definition of distinct subtypes of CLAD. In this review, recent advances in our understanding of the pathophysiological mechanisms of the different phenotypes of CLAD will be discussed with a particular focus on tissue-based and molecular studies. An overview of the current knowledge on the mechanisms of the airway-centered bronchiolitis obliterans syndrome, as well as the airway and alveolar injuries in the restrictive allograft syndrome and also the vascular compartment in chronic antibody-mediated rejection is provided. Specific attention is also given to morphological and molecular markers for early CLAD diagnosis or histological changes associated with subsequent CLAD development. Evidence for a possible overlap between different forms of CLAD is presented and discussed. In the end, "tissue remains the (main) issue," as we are still limited in our knowledge about the actual triggers and specific mechanisms of all late forms of posttransplant graft failure, a shortcoming that needs to be addressed in order to further improve the outcome of lung transplant recipients.
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Affiliation(s)
- Stijn E Verleden
- Lab of Respiratory Diseases, BREATH, Department of CHROMETA, KU Leuven, Leuven, Belgium.,Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany
| | - Jan Von der Thüsen
- Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Antoine Roux
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
| | - Emily S Brouwers
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Peter Braubach
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Mark Kuehnel
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Florian Laenger
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Danny Jonigk
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
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25
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Coiffard B, Reynaud-Gaubert M, Rey JB, Cousin E, Grosdidier C, Nicolino-Brunet C, Dignat-George F, Papazian L, Thomas PA, Barbolosi D, Serre R. Mathematical modeling of peripheral blood neutrophil kinetics to predict CLAD after lung transplantation. Transpl Immunol 2020; 62:101321. [PMID: 32711032 DOI: 10.1016/j.trim.2020.101321] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND The presence of neutrophils in the lung was identified as a factor associated with CLAD but requires invasive samples. The aim of this study was to assess the kinetics of peripheral blood neutrophils after lung transplantation as early predictor of CLAD. METHODS We retrospectively included all recipients transplanted in our center between 2009 and 2014. Kinetics of blood neutrophils were evaluated to predict early CLAD by mathematical modeling using unadjusted and adjusted analyses. RESULTS 103 patients were included, 80 in the stable group and 23 in the CLAD group. Bacterial infections at 1 year were associated with CLAD occurrence. Neutrophils demonstrated a high increase postoperatively and then a progressive decrease until normal range. Recipients with CLAD had higher neutrophil counts (mixed effect coefficient beta over 3 years = +1.36 G/L, 95% Confidence Interval [0.99-1.92], p < .001). A coefficient of celerity (S for speed) was calculated to model the kinetics of return to the norm before CLAD occurrence. After adjustment, lower values of S (slower decrease of neutrophils) were associated with CLAD (Odds Ratio = 0.26, 95% Confidence Interval [0.08-0.66], p = .01). CONCLUSION A slower return to the normal range of blood neutrophils was early associated with CLAD occurrence.
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Affiliation(s)
- Benjamin Coiffard
- Aix Marseille Univ, APHM, Hôpital Nord, Service de Pneumologie, Centre de Compétences des Maladies Pulmonaires Rares, Equipe de Transplantation Pulmonaire, Marseille, France.
| | - Martine Reynaud-Gaubert
- Aix Marseille Univ, APHM, Hôpital Nord, Service de Pneumologie, Centre de Compétences des Maladies Pulmonaires Rares, Equipe de Transplantation Pulmonaire, Marseille, France
| | - Jean-Baptiste Rey
- Aix Marseille Univ, APHM, Hôpital Nord, Service de Pneumologie, Centre de Compétences des Maladies Pulmonaires Rares, Equipe de Transplantation Pulmonaire, Marseille, France
| | - Elissa Cousin
- Aix-Marseille Univ, APHM, INSERM UMR1068, CNRS UMR7258, SMARTc-CRCM, Marseille, France
| | - Charlotte Grosdidier
- Aix Marseille Univ, APHM, Hôpital Nord, Laboratoire d'Hématologie, Marseille, France
| | - Corinne Nicolino-Brunet
- Aix Marseille Univ, APHM, Hôpital La Conception, Laboratoire d'Hématologie et de Biologie Vasculaire, Marseille, France
| | - Françoise Dignat-George
- Aix Marseille Univ, APHM, Hôpital La Conception, Laboratoire d'Hématologie et de Biologie Vasculaire, Marseille, France
| | - Laurent Papazian
- Aix Marseille Univ, APHM, Hôpital Nord, Médecine Intensive - Réanimation, Marseille, France
| | | | - Dominique Barbolosi
- Aix-Marseille Univ, APHM, INSERM UMR1068, CNRS UMR7258, SMARTc-CRCM, Marseille, France
| | - Raphaël Serre
- Aix-Marseille Univ, APHM, INSERM UMR1068, CNRS UMR7258, SMARTc-CRCM, Marseille, France
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26
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Yoshiyasu N, Sato M. Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome. World J Transplant 2020; 10:104-116. [PMID: 32864356 PMCID: PMC7428788 DOI: 10.5500/wjt.v10.i5.104] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/30/2020] [Accepted: 05/12/2020] [Indexed: 02/05/2023] Open
Abstract
Chronic lung allograft dysfunction (CLAD) following lung transplantation limits long-term survival considerably. The main reason for this is a lack of knowledge regarding the pathological condition and the establishment of treatment. The consensus statement from the International Society for Heart and Lung Transplantation on CLAD in 2019 classified CLAD into two main phenotypes: Bronchiolitis obliterans syndrome and restrictive allograft syndrome. Along with this clear classification, further exploration of the mechanisms and the development of appropriate prevention and treatment strategies for each phenotype are desired. In this review, we summarize the new definition of CLAD and update and summarize the existing knowledge on the underlying mechanisms of bronchiolitis obliterans syndrome and restrictive allograft syndrome, which have been elucidated from clinicopathological observations and animal experiments worldwide.
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Affiliation(s)
- Nobuyuki Yoshiyasu
- Department of Thoracic Surgery, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Masaaki Sato
- Department of Thoracic Surgery, The University of Tokyo Hospital, Tokyo 113-8655, Japan
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27
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Abstract
Introduction: Lung transplantation remains an important treatment for patients with end stage lung disease. Chronic lung allograft dysfunction (CLAD) remains the greatest limiting factor for long term survival. As the diagnosis of CLAD is based on pulmonary function tests, significant lung injury is required before a diagnosis is feasible, likely when irreversible damage has already occurred. Therefore, research is ongoing for early CLAD recognition, with biomarkers making up a substantial amount of this research.Areas covered: The purpose of this review is to describe available biomarkers, focusing on those which aid in predicting CLAD and distinguishing between different CLAD phenotypes. We describe biomarkers presenting in bronchial alveolar lavage (BAL) as well as circulating in peripheral blood, both of which offer an appealing alternative to lung biopsy.Expert opinion: Development of CLAD involves complex, multiple immune and nonimmune mechanisms. Therefore, evaluation of potential CLAD biomarkers serves a dual purpose: clinically, the goal remains early detection and identification of patients at increased risk. Simultaneously, biomarkers offer insight into the different mechanisms involved in the pathophysiology of CLAD, leading to the development of possible interventions. The ultimate goal is the development of both preventive and early intervention strategies for CLAD to improve the overall survival of our lung transplant recipients.
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Affiliation(s)
- Osnat Shtraichman
- Division of Pulmonary, Allergy & Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Pulmonary institute, Rabin Medical Center, Petach Tikva, Israel; Sackler School of Medicine, Tel Aviv, Israel
| | - Joshua M Diamond
- Division of Pulmonary, Allergy & Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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Sato M. Bronchiolitis obliterans syndrome and restrictive allograft syndrome after lung transplantation: why are there two distinct forms of chronic lung allograft dysfunction? ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:418. [PMID: 32355862 PMCID: PMC7186721 DOI: 10.21037/atm.2020.02.159] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Bronchiolitis obliterans syndrome (BOS) had been considered to be the representative form of chronic rejection or chronic lung allograft dysfunction (CLAD) after lung transplantation. In BOS, small airways are affected by chronic inflammation and obliterative fibrosis, whereas peripheral lung tissue remains relatively intact. However, recognition of another form of CLAD involving multiple tissue compartments in the lung, termed restrictive allograft syndrome (RAS), raised a fundamental question: why there are two phenotypes of CLAD? Increasing clinical and experimental data suggest that RAS may be a prototype of chronic rejection after lung transplantation involving both cellular and antibody-mediated alloimmune responses. Some cases of RAS are also induced by fulminant general inflammation in lung allografts. However, BOS involves alloimmune responses and the airway-centered disease process can be explained by multiple mechanisms such as external alloimmune-independent stimuli (such as infection, aspiration and air pollution), exposure of airway-specific autoantigens and airway ischemia. Localization of immune responses in different anatomical compartments in different phenotypes of CLAD might be associated with lymphoid neogenesis or the de novo formation of lymphoid tissue in lung allografts. Better understanding of distinct mechanisms of BOS and RAS will facilitate the development of effective preventive and therapeutic strategies of CLAD.
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Affiliation(s)
- Masaaki Sato
- Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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29
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Kawashima M, Juvet SC. The role of innate immunity in the long-term outcome of lung transplantation. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:412. [PMID: 32355856 PMCID: PMC7186608 DOI: 10.21037/atm.2020.03.20] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Long-term survival after lung transplantation remains suboptimal due to chronic lung allograft dysfunction (CLAD), a progressive scarring process affecting the graft. Although anti-donor alloimmunity is central to the pathogenesis of CLAD, its underlying mechanisms are not fully elucidated and it is neither preventable nor treatable using currently available immunosuppression. Recent evidence has shown that innate immune stimuli are fundamental to the development of CLAD. Here, we examine long-standing assumptions and new concepts linking innate immune activation to late lung allograft fibrosis.
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Affiliation(s)
- Mitsuaki Kawashima
- Latner Thoracic Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Stephen C Juvet
- Latner Thoracic Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
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30
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Hayes D, Harhay MO, Nicol KK, Liyanage NPM, Keller BC, Robinson RT. Lung T-Cell Profile Alterations are Associated with Bronchiolitis Obliterans Syndrome in Cystic Fibrosis Lung Transplant Recipients. Lung 2019; 198:157-161. [PMID: 31807920 DOI: 10.1007/s00408-019-00298-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 11/26/2019] [Indexed: 11/30/2022]
Abstract
The contribution of T-cells after lung transplant (LTx) remains controversial with no current consensus of their role concerning chronic lung allograft dysfunction. Using flow cytometry to assess T-cell subsets of bronchoalveolar lavage fluid (BALF) in 16 cystic fibrosis (CF) LTx recipients, we identified a decline in CD4+ T-cell frequency and an increase in CD8+ T-cell frequency in patients who developed severe bronchiolitis obliterans syndrome (BOS) (N = 10) when comparing baseline (6 months post-LTx) and follow-up (most recent bronchoscopy-clinical or surveillance per protocol). Comparing BOS to No BOS cohorts, significant differences were found in CD4+ T-cell frequency [17.4 (12.5, 28.2) vs 46.6 (44.4, 48.4), p = 0.003] and CD8+ T-cell frequency [65.6 (62.8, 75.3) vs 39.2 (32.2, 43.3), p = 0.014], respectively. The mean difference of the CD4:CD8 ratio was 0.87 units lower (95% CI - 1.44 to - 0.30, p = 0.006) than patients without BOS, while the median difference of the CD4:CD8 ratio was 0.92 units lower (95% CI - 1.83 to - 0.009, p = 0.048). Therefore, our results suggest that T-cell profiles measured through flow cytometry of BALF in the CF LTx population are associated with the development of severe BOS. Further work is needed in larger patient populations to validate our findings and to determine if this is useful for recipients who underwent LTx for other indications.
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Affiliation(s)
- Don Hayes
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. .,Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA. .,Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA. .,Section of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA. .,The Ohio State University, ED-5022, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
| | - Michael O Harhay
- Division of Pulmonary, Allergy and Critical Care and Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kathleen K Nicol
- Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.,Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | - Namal P M Liyanage
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Brian C Keller
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Richard T Robinson
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
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31
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Donor-recipient Lymphatic Interaction After Lung Transplantation: Not Simply a Drainage Route for Water, but a Complex Pathway Regulating Intrapulmonary Alloimmunity. Transplantation 2019; 104:e61-e62. [PMID: 31688667 DOI: 10.1097/tp.0000000000003045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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32
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Sacreas A, Taupin JL, Emonds MP, Daniëls L, Van Raemdonck DE, Vos R, Verleden GM, Vanaudenaerde BM, Roux A, Verleden SE. Intragraft donor-specific anti-HLA antibodies in phenotypes of chronic lung allograft dysfunction. Eur Respir J 2019; 54:13993003.00847-2019. [PMID: 31439680 DOI: 10.1183/13993003.00847-2019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 07/31/2019] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Circulating anti-human leukocyte antigen (HLA) serum donor-specific antibodies (sDSAs) increase the risk of chronic lung allograft dysfunction (CLAD) and mortality. Discrepancies between serological and pathological/clinical findings are common. Therefore, we aimed to assess the presence of tissue-bound graft DSAs (gDSAs) in CLAD explant tissue compared with sDSAs. METHODS Tissue cores, obtained from explant lungs of unused donors (n=10) and patients with bronchiolitis obliterans syndrome (BOS; n=18) and restrictive allograft syndrome (RAS; n=18), were scanned with micro-computed tomography before elution of antibodies. Total IgG levels were measured via ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples. RESULTS Overall, mean fluorescence intensity was higher in RAS eluates compared with BOS and controls (p<0.0001). In BOS, two patients were sDSA+/gDSA+ and two patients were sDSA-/gDSA+. In RAS, four patients were sDSA+/gDSA+, one patient was sDSA+/gDSA- and five patients were sDSA-/gDSA+. Serum and graft results combined, DSAs were more prevalent in RAS compared with BOS (56% versus 22%; p=0.04). There was spatial variability in gDSA detection in one BOS patient and three RAS patients, who were all sDSA-. Total graft IgG levels were higher in RAS than BOS (p<0.0001) and in gDSA+ versus gDSA- (p=0.0008), but not in sDSA+ versus sDSA- (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= -0.39; p=0.02). CONCLUSIONS This study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.
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Affiliation(s)
- Annelore Sacreas
- Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Jean-Luc Taupin
- Laboratoire d'Immunologie et Histocompatibilité, Saint-Louis Hospital, Paris, France
| | - Marie-Paule Emonds
- Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium.,Dept of Immunology and Microbiology, KU Leuven, Leuven, Belgium
| | - Liesbeth Daniëls
- Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Dirk E Van Raemdonck
- Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.,Dept of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Robin Vos
- Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Geert M Verleden
- Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Bart M Vanaudenaerde
- Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Antoine Roux
- Service de Transplantation Pulmonaire, Foch Hospital, Suresnes, France
| | - Stijn E Verleden
- Leuven Lung Transplant Group, Dept of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
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Hirzel C, Ferreira VH, L'Huillier AG, Hoschler K, Cordero E, Limaye AP, Englund JA, Reid G, Humar A, Kumar D. Humoral response to natural influenza infection in solid organ transplant recipients. Am J Transplant 2019; 19:2318-2328. [PMID: 30748090 DOI: 10.1111/ajt.15296] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/20/2019] [Accepted: 01/29/2019] [Indexed: 01/25/2023]
Abstract
The humoral immune response of transplant recipients to influenza vaccination has been studied in detail. In contrast, the hemagglutinin inhibiting (HI) antibody response evoked by natural influenza infection and its impact on viral kinetics is unknown. In this prospective, multicenter, cohort study of natural influenza infection in transplant recipients, we measured HI antibody titers at presentation and 4 weeks later. Serial nasopharyngeal viral loads were determined using a quantitative influenza A polymerase chain reaction (PCR). We analyzed 196 transplant recipients with influenza infection. In the cohort of organ transplant patients with influenza A (n = 116), seropositivity rates for strain-specific antibodies were 44.0% (95% confidence interval [CI] 31.5-53.2%) at diagnosis and 64.7% (95% CI 55.4-72.9%) 4 weeks postinfection. Seroconversion was observed in 32.8% (95% CI 24.7-41.9%) of the cases. Lung transplant recipients were more likely to seroconvert (P = .002) and vaccine recipients were less likely to seroconvert (P = .024). A subset of patients (n = 30) who were unresponsive to prior vaccination were also unresponsive to natural infection. There was no correlation between viral kinetics and antibody response. This study provides novel data on the seroresponse to influenza infection in transplant patients and its relationship to a number of parameters including a prior vaccination status, virologic measures, and clinical variables.
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Affiliation(s)
- Cedric Hirzel
- Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Victor H Ferreira
- Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Arnaud G L'Huillier
- Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | | | - Elisa Cordero
- Hospital Universitario Virgen del Rocío and Biomedicine Research Institute, Seville, Spain.,Spanish Network for Research in Infectious Diseases (REIPI), Seville, Spain
| | - Ajit P Limaye
- Division of Infectious Diseases, University of Washington, Seattle, Washington
| | - Janet A Englund
- Pediatric Infectious Diseases, Seattle Children's Hospital, Seattle, Washington
| | - Gail Reid
- Division of Infectious Diseases, Loyola University Medical Center, Chicago, Illinois
| | - Atul Humar
- Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Deepali Kumar
- Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
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Tissot A, Danger R, Claustre J, Magnan A, Brouard S. Early Identification of Chronic Lung Allograft Dysfunction: The Need of Biomarkers. Front Immunol 2019; 10:1681. [PMID: 31379869 PMCID: PMC6650588 DOI: 10.3389/fimmu.2019.01681] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/04/2019] [Indexed: 01/12/2023] Open
Abstract
A growing number of patients with end-stage lung disease have benefited from lung transplantation (LT). Improvements in organ procurement, surgical techniques and intensive care management have greatly increased short-term graft survival. However, long-term outcomes remain limited, mainly due to the onset of chronic lung allograft dysfunction (CLAD), whose diagnosis is based on permanent loss of lung function after the development of irreversible lung lesions. CLAD is associated with high mortality and morbidity, and its exact physiopathology is still only partially understood. Many researchers and clinicians have searched for CLAD biomarkers to improve diagnosis, to refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable degradation of respiratory function. Donor-specific antibodies are currently the only biomarkers used in routine clinical practice, and their significance for accurately predicting CLAD is still debated. We describe here significant studies that have highlighted potential candidates for reliable and non-invasive biomarkers of CLAD in the fields of imaging and functional monitoring, humoral immunity, cell-mediated immunity, allograft injury, airway remodeling and gene expression. Such biomarkers would improve CLAD prediction and allow differential LT management regarding CLAD risk.
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Affiliation(s)
- Adrien Tissot
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Service de Pneumologie, Institut du Thorax, CHU Nantes, Nantes, France
| | - Richard Danger
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Johanna Claustre
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Service Hospitalo-Universitaire de Pneumologie - Physiologie, CHU Grenoble Alpes, Grenoble, France
| | - Antoine Magnan
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Service de Pneumologie, Institut du Thorax, CHU Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,UMR S 1087 CNRS UMR 6291, Institut du Thorax, CHU Nantes, Université de Nantes, Nantes, France
| | - Sophie Brouard
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
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35
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Paul P, Pedini P, Lyonnet L, Di Cristofaro J, Loundou A, Pelardy M, Basire A, Dignat-George F, Chiaroni J, Thomas P, Reynaud-Gaubert M, Picard C. FCGR3A and FCGR2A Genotypes Differentially Impact Allograft Rejection and Patients' Survival After Lung Transplant. Front Immunol 2019; 10:1208. [PMID: 31249568 PMCID: PMC6582937 DOI: 10.3389/fimmu.2019.01208] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 05/13/2019] [Indexed: 01/10/2023] Open
Abstract
Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37-9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08-3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.
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Affiliation(s)
- Pascale Paul
- Department of Hematology, Hopital de la Conception, INSERM CIC-1409, Assistance Publique-Hôpitaux Marseille (AP-HM), Marseille, France.,INSERM 1263, INRA, C2VN, Aix-Marseille Université (AMU), INSERM, Marseille, France
| | - Pascal Pedini
- Établissement Français du Sang PACA-Corse 13005, Marseille, France
| | - Luc Lyonnet
- Department of Hematology, Hopital de la Conception, INSERM CIC-1409, Assistance Publique-Hôpitaux Marseille (AP-HM), Marseille, France
| | - Julie Di Cristofaro
- "Biologie des Groupes Sanguins", UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
| | - Anderson Loundou
- Département de santé Publique - EA 3279, Assistance Publique-Hôpitaux Marseille (AP-HM), Aix-Marseille Université, Marseille, France
| | - Mathieu Pelardy
- Établissement Français du Sang PACA-Corse 13005, Marseille, France
| | - Agnes Basire
- Établissement Français du Sang PACA-Corse 13005, Marseille, France
| | - Françoise Dignat-George
- Department of Hematology, Hopital de la Conception, INSERM CIC-1409, Assistance Publique-Hôpitaux Marseille (AP-HM), Marseille, France.,INSERM 1263, INRA, C2VN, Aix-Marseille Université (AMU), INSERM, Marseille, France
| | - Jacques Chiaroni
- Établissement Français du Sang PACA-Corse 13005, Marseille, France.,"Biologie des Groupes Sanguins", UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
| | - Pascal Thomas
- Service de Chirurgie Thoracique et Transplantation Pulmonaire, CHU Nord Assistance Publique-Hôpitaux Marseille (AP-HM), Aix-Marseille Université, Marseille, France
| | - Martine Reynaud-Gaubert
- Service de Pneumologie et Transplantation Pulmonaire, CHU Nord Assistance Publique-Hôpitaux Marseille (AP-HM) - IHU Méditerranée Infection Aix-Marseille-Université, Marseille, France
| | - Christophe Picard
- Établissement Français du Sang PACA-Corse 13005, Marseille, France.,"Biologie des Groupes Sanguins", UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
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Vos R, Eynde RV, Ruttens D, Verleden SE, Vanaudenaerde BM, Dupont LJ, Yserbyt J, Verbeken EK, Neyrinck AP, Van Raemdonck DE, Verleden GM. Montelukast in chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant 2019; 38:516-527. [DOI: 10.1016/j.healun.2018.11.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 12/11/2022] Open
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37
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Glanville AR, Verleden GM, Todd JL, Benden C, Calabrese F, Gottlieb J, Hachem RR, Levine D, Meloni F, Palmer SM, Roman A, Sato M, Singer LG, Tokman S, Verleden SE, von der Thüsen J, Vos R, Snell G. Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant 2019; 38:483-492. [PMID: 31027539 DOI: 10.1016/j.healun.2019.03.008] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/18/2019] [Indexed: 02/07/2023] Open
Affiliation(s)
- Allan R Glanville
- Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia
| | | | - Jamie L Todd
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, North Carolina, USA
| | | | - Fiorella Calabrese
- Department of Cardiothoracic and Vascular Sciences, University of Padova Medical School, Padova, Italy
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Member of the German Center for Lung Research, Hannover, Germany
| | - Ramsey R Hachem
- Division of Pulmonary & Critical Care, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Deborah Levine
- Pulmonary Disease and Critical Care Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
| | - Federica Meloni
- Department of Respiratory Diseases Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy
| | - Scott M Palmer
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, North Carolina, USA
| | - Antonio Roman
- Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Masaaki Sato
- Department of Thoracic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Lianne G Singer
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Sofya Tokman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
| | | | - Jan von der Thüsen
- Department of Pathology, University Medical Center, Rotterdam, The Netherlands
| | - Robin Vos
- University Hospital Gasthuisberg, Leuven, Belgium
| | - Gregory Snell
- Lung Transplant Service, The Alfred Hospital, Melbourne, Victoria, Australia
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38
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Role of 18F-FDG PET/CT in Restrictive Allograft Syndrome After Lung Transplantation. Transplantation 2019; 103:823-831. [DOI: 10.1097/tp.0000000000002393] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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39
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Validation of a post-transplant chronic lung allograft dysfunction classification system. J Heart Lung Transplant 2019; 38:166-173. [DOI: 10.1016/j.healun.2018.09.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 01/25/2023] Open
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40
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Vos R, Wuyts WA, Gheysens O, Goffin KE, Schaevers V, Verleden SE, Van Herck A, Sacreas A, Heigl T, McDonough JE, Yserbyt J, Godinas L, Dupont LJ, Neyrinck AP, Van Raemdonck DE, Verbeken EK, Vanaudenaerde BM, Verleden GM. Pirfenidone in restrictive allograft syndrome after lung transplantation: A case series. Am J Transplant 2018; 18:3045-3059. [PMID: 30019840 DOI: 10.1111/ajt.15019] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 01/25/2023]
Abstract
Pirfenidone may attenuate the decline of pulmonary function in restrictive allograft syndrome (RAS) after lung transplantation. We retrospectively assessed all lung transplant recipients with RAS who were treated with pirfenidone for at least 3 months (n = 11) in our lung transplant center and report on their long-term outcomes following initiation of pirfenidone. Main outcome parameters included evolution of pulmonary function and overall survival. Pirfenidone appears to attenuate the decline in forced vital capacity and forced expiratory volume in 1 second. Notably, 3 patients were bridged to redo-transplantation with pirfenidone for 11 (5-12) months and are currently alive, while 3 other patients demonstrate long-term stabilization of pulmonary function after 26.6 (range 18.4-46.6) months of treatment. Median overall 3-year survival after RAS diagnosis was 54.5%. Subjective intolerance, mainly anorexia and nausea, necessitating pirfenidone dose de-escalation in 55% of patients, as well as calcineurin dose increase requirements with about 20% are important complications during pirfenidone treatment after lung transplantation. Our findings provide further evidence that pirfenidone appears to be safe and may attenuate the rate of decline in lung function in patients with RAS, but the actual clinical benefit cannot be assessed in the context of this study design and requires further investigation in a larger randomized trial.
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Affiliation(s)
- Robin Vos
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Wim A Wuyts
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Olivier Gheysens
- Department of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Karolien E Goffin
- Department of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Veronique Schaevers
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Stijn E Verleden
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Anke Van Herck
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Annelore Sacreas
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Tobias Heigl
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - John E McDonough
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Jonas Yserbyt
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Laurent Godinas
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Lieven J Dupont
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Arne P Neyrinck
- Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium
| | | | | | - Bart M Vanaudenaerde
- Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Geert M Verleden
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
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41
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Walton DC, Cantwell L, Hiho S, Ta J, Wright S, Sullivan LC, Snell GI, Westall GP. HLA class II Eplet mismatch predicts De Novo DSA formation post lung transplant. Transpl Immunol 2018; 51:73-75. [PMID: 30321645 DOI: 10.1016/j.trim.2018.10.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 10/07/2018] [Accepted: 10/12/2018] [Indexed: 01/10/2023]
Abstract
The use of algorithms such as HLAMatchmaker to redefine donor-recipient HLA matching is gaining increasing attention. Our research has previously demonstrated that higher HLA class II eplet mismatches correlated with the development of chronic lung allograft dysfunction (CLAD). In this study of lung transplant recipients we prospectively examined the association between donor-recipient HLA eplet mismatches as defined by HLAMatchmaker (version 2.1) and de-novo anti-HLA donor-specific antibody (DSA) formation, as assessed by single antigen-bead solid phase assay. HLA class II eplet mismatch, when split at the median for the cohort, predicted the development of de-novo HLA class II DSA at 3 months but not at 12 months. Having previously shown that high HLA class II eplet mismatches was associated with CLAD, we now show that the same factors are associated with de-novo HLA class II DSA post-transplant.
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Affiliation(s)
- Duncan C Walton
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
| | - Linda Cantwell
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
| | - Steven Hiho
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
| | - Joseph Ta
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
| | - Stephen Wright
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
| | - Lucy C Sullivan
- Lung Transplant Service, Alfred Hospital, Melbourne, Australia; Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Greg I Snell
- Lung Transplant Service, Alfred Hospital, Melbourne, Australia
| | - Glen P Westall
- Lung Transplant Service, Alfred Hospital, Melbourne, Australia.
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42
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Parker WF, Bag R. Chronic Lung Allograft Dysfunction. CURRENT PULMONOLOGY REPORTS 2018. [DOI: 10.1007/s13665-018-0208-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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43
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Fakhro M, Broberg E, Algotsson L, Hansson L, Koul B, Gustafsson R, Wierup P, Ingemansson R, Lindstedt S. Double lung, unlike single lung transplantation might provide a protective effect on mortality and bronchiolitis obliterans syndrome. J Cardiothorac Surg 2017; 12:100. [PMID: 29178919 PMCID: PMC5702105 DOI: 10.1186/s13019-017-0666-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/16/2017] [Indexed: 12/19/2022] Open
Abstract
Background Survival after lung transplantation (LTx) is often limited by bronchiolitis obliterans syndrome (BOS). Method Survey of 278 recipients who underwent LTx. The endpoint used was BOS (BOS grade ≥ 2), death or Re-lung transplantation (Re-LTx) assessed by competing risk regression analyses. Results The incidence of BOS grade ≥ 2 among double LTx (DLTx) recipients was 16 ± 3% at 5 years, 30 ± 4% at 10 years, and 37 ± 5% at 20 years, compared to single LTx (SLTx) recipients whose corresponding incidence of BOS grade ≥ 2 was 11 ± 3%, 20 ± 4%, and 24 ± 5% at 5, 10, and 20 years, respectively (p > 0. 05). The incidence of BOS grade ≥ 2 by major indications ranked in descending order: other, PF, CF, COPD, PH and AAT1 (p < 0. 05). The mortality rate by major indication ranked in descending order: COPD, PH, AAT1, PF, Other and CF (p < 0. 05). Conclusion No differences were seen in the incidence of BOS grade ≥ 2 regarding type of transplant, however, DLTx recipients showed a better chance of survival despite developing BOS compared to SLTx recipients. The highest incidence of BOS was seen among CF, PF, COPD, PH, and AAT1 recipients in descending order, however, CF and PF recipients showed a better chance of survival despite developing BOS compared to COPD, PH, and AAT1 recipients.
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Affiliation(s)
- Mohammed Fakhro
- Department of Cardiothoracic Surgery, Skåne University Hospital, Lund University, Lund, Sweden.
| | - Ellen Broberg
- Department of Thoracic Intensive Care and Anesthesia, Skåne University Hospital, Lund University, Lund, Sweden
| | - Lars Algotsson
- Department of Thoracic Intensive Care and Anesthesia, Skåne University Hospital, Lund University, Lund, Sweden
| | - Lennart Hansson
- Department of Pulmonary Medicine, Skåne University Hospital, Lund University, Lund, Sweden
| | - Bansi Koul
- Department of Cardiothoracic Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - Ronny Gustafsson
- Department of Cardiothoracic Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - Per Wierup
- Department of Cardiothoracic Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - Richard Ingemansson
- Department of Cardiothoracic Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - Sandra Lindstedt
- Department of Cardiothoracic Surgery, Skåne University Hospital, Lund University, Lund, Sweden
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Verleden SE, Vanaudenaerde BM, Emonds MP, Van Raemdonck DE, Neyrinck AP, Verleden GM, Vos R. Donor-specific and -nonspecific HLA antibodies and outcome post lung transplantation. Eur Respir J 2017; 50:50/5/1701248. [PMID: 29146602 DOI: 10.1183/13993003.01248-2017] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 08/11/2017] [Indexed: 12/31/2022]
Abstract
Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) are associated with chronic lung allograft dysfunction (CLAD) and mortality post lung transplantation, but data concerning prevalence, time of onset, persistence and effects on long-term outcome remain scarce.We assessed the association between HLA antibodies and CLAD-free and graft survival in a cohort of 362 patients. We stratified our analysis according to DSA status, persistence of antibodies and timing of antibodies (pre-transplant, early or late post-transplant).Within our cohort, 61 (17%) patients developed DSAs (mostly against HLA-DQ), which was associated with worse CLAD-free and graft survival (p<0.0001 and p=0.059, respectively). Persistent (hazard ratio (HR) 3.386, 95% CI 1.928-5.948; p<0.0001) as well as transient (HR 2.998, 95% CI 1.406-6.393; p=0.0045) DSAs were associated with shorter CLAD-free survival compared with patients without DSAs. Persistent DSAs (HR 3.071, 95% CI 1.632-5.778; p=0.0005) but not transient DSAs were negatively associated with graft survival compared with patients without DSAs, likely due to the higher incidence of restrictive CLAD. HLA non-DSAs and pre-transplant HLA antibodies had no effect on post-transplant outcome.We demonstrated an important difference in prognosis between persistent and transient DSAs. Moreover, the observed association between DSAs and restrictive CLAD suggests an overlap between antibody-mediated rejection and restrictive CLAD that needs further investigation.
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Affiliation(s)
- Stijn E Verleden
- Lung Transplant Unit, Division of Respiratory Disease, Dept of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Bart M Vanaudenaerde
- Lung Transplant Unit, Division of Respiratory Disease, Dept of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Marie-Paul Emonds
- HILA laboratory, Rode Kruis Vlaanderen, Mechelen, Belgium.,Dept of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Dirk E Van Raemdonck
- Lung Transplant Unit, Division of Respiratory Disease, Dept of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Arne P Neyrinck
- Lung Transplant Unit, Division of Respiratory Disease, Dept of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Geert M Verleden
- Lung Transplant Unit, Division of Respiratory Disease, Dept of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Robin Vos
- Lung Transplant Unit, Division of Respiratory Disease, Dept of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
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45
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Verleden SE, Vos R, Vanaudenaerde BM, Verleden GM. Chronic lung allograft dysfunction phenotypes and treatment. J Thorac Dis 2017; 9:2650-2659. [PMID: 28932572 DOI: 10.21037/jtd.2017.07.81] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Chronic lung allograft dysfunction (CLAD) remains a major hurdle limiting long-term survival post lung transplantation. Given the clinical heterogeneity of CLAD, recently two phenotypes of CLAD have been defined [bronchiolitis obliterans syndrome (BOS) vs. restrictive allograft syndrome (RAS) or restrictive CLAD (rCLAD)]. BOS is characterized by an obstructive pulmonary function, air trapping on CT and obliterative bronchiolitis (OB) on histopathology, while RAS/rCLAD patients show a restrictive pulmonary function, persistent pleuro-parenchymal infiltrates on CT and pleuroparenchymal fibro-elastosis on biopsies. Importantly, the patients with RAS/rCLAD have a severely limited survival post diagnosis of 6-18 months compared to 3-5 years after BOS diagnosis. In this review, we will review historical evidence for this heterogeneity and we will highlight the clinical, radiological, histopathological characteristics of both phenotypes, as well as their risk factors. Treatment of CLAD remains troublesome, nevertheless, we will give an overview of different treatment strategies that have been tried with some success. Adequate phenotyping remains difficult but is clearly needed for both clinical and scientific purposes.
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Affiliation(s)
- Stijn E Verleden
- Department of Clinical and Experimental Medicine, Lung Transplant Unit, KU Leuven, Leuven, Belgium
| | - Robin Vos
- Department of Clinical and Experimental Medicine, Lung Transplant Unit, KU Leuven, Leuven, Belgium
| | - Bart M Vanaudenaerde
- Department of Clinical and Experimental Medicine, Lung Transplant Unit, KU Leuven, Leuven, Belgium
| | - Geert M Verleden
- Department of Clinical and Experimental Medicine, Lung Transplant Unit, KU Leuven, Leuven, Belgium
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47
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Advanced Role of Neutrophils in Common Respiratory Diseases. J Immunol Res 2017; 2017:6710278. [PMID: 28589151 PMCID: PMC5447318 DOI: 10.1155/2017/6710278] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/22/2017] [Accepted: 04/16/2017] [Indexed: 12/18/2022] Open
Abstract
Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases.
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Gohy ST, Ladjemi MZ, Pilette C. Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria? Eur Respir J 2017; 49:49/4/1700380. [PMID: 28446564 DOI: 10.1183/13993003.00380-2017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 02/25/2017] [Indexed: 11/05/2022]
Affiliation(s)
- Sophie T Gohy
- Institute of Experimental and Clinical Research - Pole of Pneumology, ENT and Dermatology, Université catholique de Louvain (UCL), Brussels, Belgium.,Dept of Pneumology, Cliniques universitaires St-Luc, Brussels, Belgium.,Cystic fibrosis reference center, Cliniques universitaires St-Luc, Brussels, Belgium
| | - Maha Z Ladjemi
- UMR Inserm U1152, Labex Inflammex, Université Paris 7, Paris Diderot, Paris, France
| | - Charles Pilette
- Institute of Experimental and Clinical Research - Pole of Pneumology, ENT and Dermatology, Université catholique de Louvain (UCL), Brussels, Belgium .,Dept of Pneumology, Cliniques universitaires St-Luc, Brussels, Belgium.,Institute for Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Brussels, Belgium
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