Browse
Submit Data
Databases
API
Help

Dataset Information

30 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Distinct molecular and immunological properties of circulating exosomes isolated from pediatric lung transplant recipients with bronchiolitis obliterans syndrome - a retrospective study.

ABSTRACT: Long-term success following human lung transplantation is poor due to chronic rejection. We demonstrated circulating exosomes of lung origin during acute and chronic lung allograft rejection. We analyzed plasma from pediatric lung transplant recipients (LTxRs) enrolled in the CTOT-C-03 to determine whether circulating exosomes are released into circulation during bronchiolitis obliterans syndrome (BOS). Plasma exosomes were isolated, and human leukocyte antigens (HLA) were detected. Exosomes were analyzed for lung self-antigens (SAgs), co-stimulatory molecules transcription factors, major histocompatibility complex class II (MHC-II), adhesion molecules, and 20S proteasome. Mice were immunized with exosomes from BOS or stable to determine their immunogenicity. Circulating exosomes from BOS LTxRs contained increased levels of SAgs, donor HLA class I, MHC-II, transcription factors, co-stimulatory molecules, and 20S proteasome compared with stable. Serial analysis of exosomes containing SAgs demonstrated that exosomes are detectable in the circulation before BOS. Mice immunized with exosomes from BOS, or stable, demonstrated that exosomes from BOS are distinct in inducing both humoral and cellular immune responses to SAgs. Circulating exosomes from BOS LTxRs elicit distinct humoral and cellular response. In addition, detection of SAgs on circulatory exosomes 12 months before diagnosis of BOS suggest that exosomes could serve as biomarker.

SUBMITTER: Sharma M

PROVIDER: S-EPMC8443129 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients.

Project description:RationaleDespite the importance of bronchiolitis obliterans syndrome (BOS) in lung transplantation, little is known regarding the factors that influence survival after the onset of this condition, particularly among bilateral transplant recipients.ObjectivesTo identify factors that influence survival after the onset of BOS among bilateral lung transplant recipients.MethodsThe effect of demographic or clinical factors, occurring before BOS, upon survival after the onset of BOS was studied in 95 bilateral lung transplant recipient using Cox proportional hazards models.Measurements and main resultsAlthough many factors, including prior acute rejection or rejection treatments, were not associated with survival after BOS, BOS onset within 2 years of transplantation (early-onset BOS), or BOS onset grade of 2 or 3 (high-grade onset) were predictive of significantly worse survival (early onset P = 0.04; hazard ratio, 1.84; 95% confidence interval, 1.03-3.29; high-grade onset P = 0.003; hazard ratio, 2.40; 95% confidence interval, 1.34-4.32). The effects of both early onset and high-grade onset on survival persisted in multivariable analysis and after adjustment for concurrent treatments. Results suggested an interaction might exist between early onset and high-grade onset. In particular, high-grade onset of BOS, regardless of its timing after transplant, is associated with a very poor prognosis.ConclusionsThe course of BOS after bilateral lung transplantation is variable. Distinct patterns of survival after BOS are evident and related to timing or severity of onset. Further characterization of these subgroups should provide a more rational basis from which to design, stratify, and assess response in future BOS treatment trials.

| S-EPMC2949403 | biostudies-literature

The mononuclear phagocyte system contributes to fibrosis in post-transplant Obliterans Bronchiolitis

Project description:Bronchiolitis Obliterans Syndrome (BOS) is a fibrotic disease heavily responsible for high mortality rates after lung transplantation. Myofibroblasts are primary effectors of this fibrotic process, but their origin is still under debate. The purpose of this work was to identify the precursors of mesenchymal cells responsible for post-transplant airway fibro-obliteration. Lineage-tracing tools were used to track or deplete potential sources of myofibroblasts in the heterotopic tracheal transplantation model. Allografts were analysed by histology, confocal microscopy, flow cytometry or single-cell transcriptomic analysis. BOS explants were evaluated by histology and confocal microscopy. Myofibroblasts in the allografts were recipient-derived. Still, when recipient mice were treated with tacrolimus, we observed rare epithelial-to-mesenchymal transition phenomena and an increase in donor-derived myofibroblasts (P=0.0467), but the proportion of these cells remained low (7%). Hematopoietic cells, and specifically the mononuclear phagocyte system, gave rise to the majority of myofibroblasts found in occluded airways. Ablation of Cx3cR1+ cells decreased fibro-obliteration (P=0.0151) and myofibroblasts accumulation (P=0.0020). Single-cell RNA-sequencing unveiled similarities between myeloid-derived cells from allografts and both murine and human samples of lung fibrosis. Finally, myofibroblasts expressing the macrophage marker CD68 were increased in BOS explants when compared to controls (13% vs 2.3%, P=0.0007). Recipient-derived myeloid progenitors represent a clinically-relevant source of mesenchymal cells infiltrating the airways after allogeneic transplantation. Therefore, therapies targeting the mononuclear phagocyte system could improve long-term outcomes after lung transplantation.

2020-11-04 | GSE160760 | GEO

Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome.

Project description:Lung transplantation, in patients with end-stage lung disease, is limited by chronic rejection, which occurs with an incidence and severity exceeding most other transplanted organs. Alloimmune responses play an important role in progression to chronic rejection that manifests as bronchiolitis obliterans syndrome (BOS), but no biomarker can currently predict the progression to BOS. Studies in animal models suggest that intragraft T regulatory cells (Tregs) are important in maintaining transplantation tolerance, and FoxP3 is the protoypic Treg marker.Leukocytes in blood and bronchoalveolar lavage (BAL) fluid were compared for expression of FoxP3 by flow cytometry in 14 stable lung transplant recipients and 6 lung transplant recipients who eventually developed BOS.Stable patients, compared with patients who subsequently developed BOS, consistently had a significantly increased percentage of FoxP3 cells among CD4 cells in BAL and greater levels of the Treg-attracting chemokine CCL22. These differences were observed in limited sequential analyses, before, at the time of acute rejection, and postacute rejection. In this pilot study, a threshold of 3.2% CD4/FoxP3 cells in the BAL distinguished stable recipients from those subsequently developing BOS within the first 2 years posttransplantation.The proportion of FoxP3 cells among CD4 cells in BAL may help to predict lung allograft outcome and guide therapeutic immunosuppression in lung transplant recipients.

| S-EPMC4737704 | biostudies-literature

Beyond Bronchiolitis Obliterans: In-Depth Histopathologic Characterization of Bronchiolitis Obliterans Syndrome after Lung Transplantation.

Project description:Bronchiolitis obliterans syndrome (BOS) is considered an airway-centered disease, with bronchiolitis obliterans (BO) as pathologic hallmark. However, the histologic spectrum of pure clinical BOS remains poorly characterized. We provide the first in-depth histopathologic description of well-characterized BOS patients and patients without chronic lung allograft dysfunction (CLAD), defined according to the recent consensus guidelines. Explant lung tissue from 52 clinically-defined BOS and 26 non-CLAD patients (collected 1993-2018) was analyzed for histologic parameters, including but not limited to airway lesions, vasculopathy and fibrosis. In BOS, BO lesions were evident in 38 (73%) patients and varied from concentric sub-epithelial fibrotic BO to inflammatory BO, while 10/14 patients without BO displayed 'vanishing airways', defined by a discordance between arteries and airways. Chronic vascular abnormalities were detected in 22 (42%) patients. Ashcroft fibrosis scores revealed a median of 43% (IQR: 23-69) of normal lung parenchyma per patient; 26% (IQR: 18-37) of minimal alveolar fibrous thickening; and 11% (IQR: 4-18) of moderate alveolar thickening without architectural damage. Patchy areas of definite fibrotic damage to the lung structure (i.e., Ashcroft score ≥5) were present in 28 (54%) patients. Fibrosis was classified as bronchocentric (n = 21/28, 75%), paraseptal (n = 17/28, 61%) and subpleural (n = 15/28, 54%). In non-CLAD patients, BO lesions were absent, chronic vascular abnormalities present in 1 (4%) patient and mean Ashcroft scores were significantly lower compared to BOS (p = 0.0038) with 78% (IQR: 64-88) normally preserved lung parenchyma. BOS explant lungs revealed evidence of various histopathologic findings, including vasculopathy and fibrotic changes, which may contribute to the pathophysiology of BOS.

| S-EPMC8745215 | biostudies-literature

Global Proteomics Analysis of Circulating Extracellular Vesicles Isolated from Lung Transplant Recipients.

Project description:Lung transplant recipients (LTxRs) with acute rejection (AR) and chronic rejection (bronchiolitis obliterans syndrome [BOS]) induce circulating exosomes known to contain donor human leukocyte antigens and lung-associated self-antigens. Here, we sought to identify proteomic signatures in circulating extracellular vesicles (EVs) that differentiate LTxRs in 4 groups: stable, AR, BOS, or respiratory viral infection (RVI). EVs were isolated from plasma from patients in each group via ultracentrifugation. EV protein cargoes were prepared for shotgun proteomics using liquid chromatography-tandem mass spectrometry. We identified 2 unique proteins for AR, 4 for RVI, 24 for BOS, and 8 for stable LTxRs. Differential analysis of AR, BOS, RVI, and stable proteins identified significantly deregulated proteins (p < 0.05, log2(fold change) > ±1) in each condition (31, 2, and 2, respectively). EVs from LTxRs with AR contained proteins involved in immunoglobulin, complement regulation, coagulation, and innate and adaptive immune response pathways. EVs from LTxRs with BOS revealed enriched immunoglobulin receptors and a carboxypeptidase N catalytic chain. EVs from LTxRs with RVI had an enriched macrophage-stimulating factor. We found unique signatures in LTxRs with AR, BOS, and RVI, highlighting complex immune mechanisms underlying lung allograft rejection. Proteomic signatures in LTxRs' circulating EVs provided insights into immunological mechanisms of graft rejection and RVI.

| S-EPMC7315412 | biostudies-literature

Mycoplasma pneumoniae-Associated Bronchiolitis Obliterans Following Acute Bronchiolitis.

Project description:The characteristics of Mycoplasma pneumonia (M. pneumoniae)-associated bronchiolitis obliterans (BO) are not well known. We retrospectively reviewed 17 patients with M. pneumoniae-associated BO. All patients had M. pneumoniae-associated acute bronchiolitis prior to the development of BO. In the acute bronchiolitis stage, all patients had fever and cough; six patients also had wheezing and dyspnoea. BO was diagnosed approximately 1.5-8 months later based on clinical manifestations and chest high-resolution computed tomography (HRCT) findings. All patients presented with wheezing and/or dyspnoea at the time of diagnosis of BO. HRCT findings included mosaic attenuation, pronounced air trapping, central bronchiectasis and emphysema, according to disease severity. Lung function tests revealed mild to severe airway obstruction. Fourteen of 17 patients had a greater than 12% increase in forced expiratory volume in 1 second values after taking salbutamol. All patients had positive allergy test results and family or personal history of atopic disease. Four patients had a history of asthma before M. pneumonia bronchiolitis. Asthma was diagnosed before, at the time of or after the diagnosis of BO in 11 cases. M. pneumoniae-associated BO may therefore develop following M. pneumonia bronchiolitis and overlap with asthma.

| S-EPMC5559585 | biostudies-other

Adenoviral infections in pediatric liver transplant recipients.

Project description:Over a 5 1/2-year period, 22 of 262 children receiving liver transplants developed adenoviral infections. Five had adenoviral hepatitis in the allograft, caused by serotype 5. All five were treated for rejection, either just before or at the time of infection. Liver biopsy specimens had characteristic histological appearance, and diagnosis of adenoviral infection was confirmed with monoclonal antiadenoviral antibodies, electron microscopy, and by culture of liver tissue. In the remaining 17 patients, adenovirus was isolated from urine, stool, throat secretions, and/or blood samples, but none had any detectable visceral infection. Serotypes 1 and 2 predominated, similar to children not receiving transplants during the same time period. Three of the patients with hepatitis are alive and well; two died of liver failure. Adenoviral hepatitis did not recur in the second allograft of a patient who underwent retransplantation for combined rejection and adenoviral hepatitis, and appears, therefore, not to be a contraindication to retransplantation when liver failure ensues.

| S-EPMC2964055 | biostudies-other

Pediatric lung transplantation: Dynamics of the microbiome and bronchiolitis obliterans in cystic fibrosis.

Project description:BackgroundCompositional changes in the microbiome are associated with the development of bronchiolitis obliterans (BO) after lung transplantation (LTx) in adults with cystic fibrosis (CF). The association between the lower airway bacterial community and BO after LTx in children with CF remains largely unexplored and is possibly influenced by frequent antibiotic therapy. The objectives of this study were to examine the relationship between bacterial community dynamics and the development of BO and analyze antibiotic resistance trends in children after LTx for CF.MethodsFor 3 years from the time of transplant, 12 LTx recipients were followed longitudinally, with 5 subjects developing BO during the study period. A total of 82 longitudinal bronchoalveolar lavage samples were collected during standard of care bronchoscopies. Metagenomic shotgun sequencing was performed on the extracted microbial DNA from bronchoalveolar lavage specimens. Taxonomic profiling was constructed using WEVOTE pipeline. The longitudinal association between development of BO and temporal changes in bacterial diversity and abundance were evaluated with MetaLonDA. The analysis of antibiotic resistance genes was performed with the ARGs-OAP v2.0 pipeline.ResultsAll recipients demonstrated a Proteobacteria-predominant lower airways community. Temporal reduction in bacterial diversity was significantly associated with the development of BO and associated with neutrophilia and antibiotic therapy. Conversely, an increasing abundance of the phylum Actinobacteria and the orders Neisseriales and Pseudonocardiales in the lower airways was significantly associated with resilience to BO. A more diverse bacterial community was related to a higher expression of multidrug resistance genes and increased proteobacterial abundance.ConclusionsDecreased diversity within bacterial communities may suggest a contribution to pediatric lung allograft rejection in CF.

| S-EPMC7437357 | biostudies-literature

Antiviral Therapeutics in Pediatric Transplant Recipients.

Project description:Recipients of solid organ and hematopoietic stem cell transplantation undergo substantial immune suppression, placing them at risk for opportunistic viral infection. Few randomized controlled trials have been dedicated to the treatment of viral infections in children, and current practices are extrapolated from data generated from adult patients. Here we discuss the prevention and treatment of viral infections using available antiviral drugs, as well as novel agents that may provide benefit to pediatric patients in the future.

| S-EPMC8900721 | biostudies-literature

Impact of Lung Function Decline on Mortality in Lung Transplant Recipients: Long-Term Results From the L-CsA-i Study for the Prevention of Bronchiolitis Obliterans Syndrome.

Project description:BackgroundChronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx).Methods10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis.ResultsA total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk.ConclusionBased on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.

| S-EPMC9201567 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data