Publications by authors named "S Sam Weigt"

90 Publications

Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data.

Transplant Direct 2020 Oct 24;6(10):e608. Epub 2020 Sep 24.

David Geffen-UCLA School of Medicine, CareDx, Inc., Los Angeles, CA.

Telehealth platforms with remote phlebotomy and biomarker implementation represent a novel paradigm for surveillance after lung transplantation (LT). In a pilot study, we investigated donor-derived cell-free DNA (dd-cfDNA) in plasma using a clinical-grade "next-generation sequencing" assay.

Methods: dd-cfDNA levels determined in biorepository venous plasma samples obtained during the lung allograft rejection gene expression observation study, implementing a clinical-grade next-generation sequencing assay. Sixty-nine unique LT patients encompassing 9 LT centers, with associated clinical-histopathologic diagnoses, were examined-allograft infection (n = 26), normal histopathology without infection (n = 30), and acute cellular rejection (ACR; n = 13).

Results: dd-cfDNA in ACR patients were significantly elevated (1.52%; interquartile range [IQR], 0.520-2.2550) compared with the normal stable patients (0.485%; IQR, 0.220-0.790) ( = 0.026). During allograft infection, dd-cfDNA values were not different (0.595; IQR, 0.270-1.170) from normal ( = 0.282) and ACR ( = 0.100). AUC-receiver operator characteristics curve analysis for allograft ACR was 0.717 (95% confidence interval, 0.547-0.887;  = 0.025). At a 0.87% threshold dd-cfDNA-sensitivity = 73.1%, specificity = 52.9%, positive predictive value = 34.1%, and negative predictive value = 85.5%.

Conclusions: dd-cfDNA assessment holds promise as a noninvasive biomarker of "allograft injury" with acute rejection following LT while prospective, multicenter studies should further refine utility across the spectrum of allograft rejection and infection.
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http://dx.doi.org/10.1097/TXD.0000000000001063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515612PMC
October 2020

Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 03;203(6):707-717

Women's Guild Lung Institute, Department of Medicine.

Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers, and cellular senescence are implicated in the pathogenies of IPF. We sought to investigate the role of alveolar type 2 (AT2) cellular senescence in initiation and/or progression of pulmonary fibrosis and therapeutic potential of targeting senescence-related pathways and senescent cells. Epithelial cells of 9 control donor proximal and distal lung tissues and 11 IPF fibrotic lung tissues were profiled by single-cell RNA sequencing to assesses the contribution of epithelial cells to the senescent cell fraction for IPF. A novel mouse model of conditional AT2 cell senescence was generated to study the role of cellular senescence in pulmonary fibrosis. We show that AT2 cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis. Senescence of AT2 cells is sufficient to drive progressive pulmonary fibrosis. Early attenuation of senescence-related pathways and elimination of senescent cells are promising therapeutic approaches to prevent pulmonary fibrosis.
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http://dx.doi.org/10.1164/rccm.202004-1274OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958503PMC
March 2021

International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation.

J Heart Lung Transplant 2020 Jul 15. Epub 2020 Jul 15.

Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics.
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http://dx.doi.org/10.1016/j.healun.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361106PMC
July 2020

Bronchoalveolar bile acid and inflammatory markers to identify high-risk lung transplant recipients with reflux and microaspiration.

J Heart Lung Transplant 2020 09 19;39(9):934-944. Epub 2020 May 19.

Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background: Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids-putative markers of gastric microaspiration-and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery.

Methods: We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay.

Results: At 3 months after transplantation, TCA, IL-1β, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery.

Conclusions: Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation.
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http://dx.doi.org/10.1016/j.healun.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483994PMC
September 2020

Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study.

Am J Respir Crit Care Med 2020 08;202(4):576-585

University of California Los Angeles, Los Angeles, California.

Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction. To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort. We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence. During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06;  ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57;  ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year. We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.
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http://dx.doi.org/10.1164/rccm.201910-1915OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427399PMC
August 2020

Highlights from the clinical trials in organ transplantation (CTOT)-20 and CTOT-22 Consortium studies in lung transplant.

Am J Transplant 2020 06;20(6):1489-1494

Duke University, Durham, North Carolina.

Long-term survival after lung transplant lags behind that of other commonly transplanted organs, reflecting the current incomplete understanding of the mechanisms involved in the development of posttransplant lung injury, rejection, infection, and chronic allograft dysfunction. To address this unmet need, 2 ongoing National Institute of Allergy and Infectious Disease funded studies through the Clinical Trials in Organ Transplant Consortium (CTOT) CTOT-20 and CTOT-22 were dedicated to understanding the clinical factors and biological mechanisms that drive chronic lung allograft dysfunction and those that maintain cytomegalovirus polyfunctional protective immunity. The CTOT-20 and CTOT-22 studies enrolled 800 lung transplant recipients at 5 North American centers over 3 years. Given the number and complexity of subjects included, CTOT-20 and CTOT-22 utilized innovative data transfers and capitalized on patient-entered data collection to minimize site manual data entry. The data were coupled with an extensive biosample collection strategy that included DNA, RNA, plasma, serum, bronchoalveolar lavage fluid, and bronchoalveolar lavage cell pellet. This Special Article describes the CTOT-20 and CTOT-22 protocols, data and biosample strategy, initial results, and lessons learned through study execution.
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http://dx.doi.org/10.1111/ajt.15957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323580PMC
June 2020

Demystifying "bad luck": Seemingly unrelated risk factors for CLAD may be connected by a common pathway.

Am J Transplant 2020 04 30;20(4):920-921. Epub 2019 Dec 30.

Duke University, Durham, North Carolina.

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http://dx.doi.org/10.1111/ajt.15741DOI Listing
April 2020

Capillary Proliferation in Systemic-Sclerosis-Related Pulmonary Fibrosis: Association with Pulmonary Hypertension.

ACR Open Rheumatol 2019 Mar 15;1(1):26-36. Epub 2019 Mar 15.

University of California Los Angeles.

Objective: We sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)-related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH).

Methods: Two pulmonary pathologists blindly evaluated 360 histologic slides from lungs of 31 SSc-PF explants or autopsies with (n = 22) and without (n = 9) PH. The presence of abnormal small arteries, veins, and capillaries (pulmonary microcirculation) was semiquantitatively assessed in areas of preserved lung architecture. Capillary proliferation (CP) within the alveolar walls was measured by its distribution, extent (CP % involvement), and maximum number of layers (maximum CP). These measures were then evaluated to determine the strength of their association with right heart catheterization-proven PH.

Results: Using consensus measures, all measures of CP were significantly associated with PH. Maximum CP had the strongest association with PH ( = 0.013; C statistic 0.869). Maximum CP 2 or more layers and CP % involvement 10% or greater were the optimal thresholds that predicted PH, both with a sensitivity of 56% and specificity of 91%. The CP was typically multifocal rather than focal or diffuse and was associated with a background pattern of usual interstitial pneumonia. There was a significant but weaker relationship between the presence of abnormal small arteries and veins and PH.

Conclusion: In the setting of advanced SSc-PF, the histopathologic feature of the pulmonary microcirculation best associated with PH was capillary proliferation in architecturally preserved lung areas.
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http://dx.doi.org/10.1002/acr2.1003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858021PMC
March 2019

Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease.

EBioMedicine 2019 Dec 12;50:379-386. Epub 2019 Nov 12.

Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA. Electronic address:

Background: Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology.

Methods: We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex.

Findings: The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs.

Interpretation: Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45-50%).

Funding: Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).
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http://dx.doi.org/10.1016/j.ebiom.2019.10.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921223PMC
December 2019

Amphiregulin contributes to airway remodeling in chronic allograft dysfunction after lung transplantation.

Am J Transplant 2020 03 1;20(3):825-833. Epub 2019 Dec 1.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina.

Chronic lung allograft dysfunction (CLAD), a condition of excess matrix deposition and airways fibrosis, limits survival after lung transplantation. Amphiregulin (Areg) is an epidermal growth factor receptor (EGFR) ligand suggested to regulate airway injury and repair. We sought to determine whether Areg expression increases in CLAD, localize the cellular source of Areg induction in CLAD, and assess its effects on airway matrix deposition. Lung fluid Areg protein was quantified in patients with or without CLAD. In situ hybridization was performed to localize Areg and EGFR transcript in CLAD and normal lung tissue. Expression of hyaluronan, a matrix constituent that accumulates in CLAD, was measured in Areg-exposed bronchial epithelial cells in the presence or absence of an EGFR inhibitor. We demonstrated that lung fluid Areg protein was significantly increased in CLAD in a discovery and replication cohort. Areg and EGFR transcripts were abundantly expressed within CLAD tissue, localized to basally distributed airway epithelial cells overlying fibrotic regions. Areg-exposed bronchial epithelial cells increased hyaluronan and hyaluronan synthase expression in an EGFR-dependent manner. Collectively, these novel observations suggest that Areg contributes to airway remodeling and CLAD. Moreover these data implicate a role for EGFR signaling in CLAD pathogenesis, suggesting novel therapeutic targets.
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http://dx.doi.org/10.1111/ajt.15667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042065PMC
March 2020

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

Am J Respir Cell Mol Biol 2020 03;62(3):364-372

Department of Medicine.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.
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http://dx.doi.org/10.1165/rcmb.2019-0140OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055700PMC
March 2020

Prediction of idiopathic pulmonary fibrosis progression using early quantitative changes on CT imaging for a short term of clinical 18-24-month follow-ups.

Eur Radiol 2020 Feb 26;30(2):726-734. Epub 2019 Aug 26.

David Geffen School of Medicine, Radiological Science, UCLA, 924 Westwood Blvd. Ste 650, Box 957319, Los Angeles, CA, 90095-7319, USA.

Objective: High-resolution computed tomography (HRCT) plays an indispensable role in the diagnosis of idiopathic pulmonary fibrosis (IPF). Due to unpredictability in progression and the short median survival of 2-5 years, it is critical to delineate the patients with rapid progression. The aim is to evaluate the predictability of IPF progression using the early quantitative changes.

Methods: Automated texture-based quantitative lung fibrosis (QLF) was calculated from the anonymized HRCT. Two datasets were collected retrospectively: (1) a pilot study of 35 subjects with three sequential scans (baseline and 6 and 12 months) to obtain a threshold, where visual assessments were stable at 6 months but worsened at 12 months; (2) 157 independent subjects to test the threshold. Landmark Cox regressions were used to compare the progression-free survival (PFS) defined by pulmonary function using the threshold from the early changes in QLF. C-indexes were reported as estimations of the concordance of prediction.

Results: A threshold of 4% QLF change at 6 months corresponded to the mean change that worsened on HRCT visually at 12 months from the pilot study. Using the threshold, significant differences were found in the independent dataset (hazard ratio (HZ) = 5.92, p = 0.001 by Cox model, C-index = 0.71 at the most severe lobe; and HZ = 3.22, p = 0.012, C-index = 0.68 in the whole lung). Median PFS was 11.9 months for subjects with ≥ 4% changes, whereas median PFS was greater than 18 months for subjects with < 4% changes at the most severe lobe.

Conclusion: Early structural changes on HRCT using a quantitative score can predict progression in lung function.

Key Points: • Changes on HRCT using quantitative texture-based scores can play a pivotal role for providing information and an aid tool for timely management decision for patients with IPF. • Quantitative changes on HRCT of 4% or more, which matched 6-month prior changes with visual assessment of worsening, can play a pivotal role for providing prediction of clinical progression by 3-5 folds higher in the next incidence, compared with those of subjects with less than 4% changes. • Early structural changes of 4% or more in a paired HRCT scans derived by quantitative scores can predict the progression in lung function in 1-2 years in subjects with IPF, which is critical information for timely management decision for subjects with IPF where the median survival is 2 to 5 years.
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http://dx.doi.org/10.1007/s00330-019-06402-6DOI Listing
February 2020

Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection.

J Heart Lung Transplant 2019 08 7;38(8):845-855. Epub 2019 May 7.

Departments of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Background: Chronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD.

Methods: We performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC).

Results: Differential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29-4.53).

Conclusions: BAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD.
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http://dx.doi.org/10.1016/j.healun.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663624PMC
August 2019

CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection.

JCI Insight 2019 05 14;5. Epub 2019 May 14.

Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Despite current immunosuppressive strategies, long-term lung transplant outcomes remain poor due to rapid allogenic responses. Using a stringent mouse model of allo-airway transplantation, we identify the CCR4-ligand axis as a central node driving secondary lymphoid tissue homing and activation of the allogeneic T cells that prevent long-term allograft survival. CCR4 deficiency on transplant recipient T cells diminishes allograft injury and when combined with CTLA4-Ig leads to an unprecedented long-term lung allograft accommodation. Thus, we identify CCR4-ligand interactions as a central mechanism driving allogeneic transplant rejection and suggest it as a potential target to enhance long-term lung transplant survival.
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http://dx.doi.org/10.1172/jci.insight.121782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629140PMC
May 2019

Molecular diagnostics for lung transplant rejection: An information pipeline or a pipe dream?

J Heart Lung Transplant 2019 05;38(5):514-515

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

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http://dx.doi.org/10.1016/j.healun.2019.02.014DOI Listing
May 2019

Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis.

PLoS One 2018 20;13(11):e0206545. Epub 2018 Nov 20.

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Background: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial.

Methods: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed.

Results: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH.

Conclusion: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206545PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245508PMC
April 2019

Bronchiolitis obliterans syndrome susceptibility and the pulmonary microbiome.

J Heart Lung Transplant 2018 09 26;37(9):1131-1140. Epub 2018 Apr 26.

Division of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Surgery, University of Illinois at Chicago, Chicago, Illinois. Electronic address:

Background: Lung transplantation outcomes remain complicated by bronchiolitis obliterans syndrome (BOS), a major cause of mortality and retransplantation for patients. A variety of factors linking inflammation and BOS have emerged, meriting further exploration of the microbiome as a source of inflammation. In this analysis, we determined features of the pulmonary microbiome associated with BOS susceptibility.

Methods: Bronchoalveolar lavage (BAL) samples were collected from 25 patients during standard of care bronchoscopies before BOS onset. Microbial DNA was isolated from BAL fluid and prepared for metagenomics shotgun sequencing. Patient microbiomes were phenotyped using k-means clustering and compared to determine effects on BOS-free survival.

Results: Clustering identified 3 microbiome phenotypes: Actinobacteria dominant (AD), mixed, and Proteobacteria dominant. AD microbiomes, distinguished by enrichment with Gram-positive organisms, conferred reduced odds and risks for patients to develop acute rejection and BOS compared with non-AD microbiomes. These findings were independent of treatment models. Microbiome findings were correlated with BAL cell counts and polymorphonuclear cell percentages.

Conclusions: In some populations, features of the microbiome may be used to assess BOS susceptibility. Namely, a Gram-positive enriched pulmonary microbiome may predict resilience to BOS.
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http://dx.doi.org/10.1016/j.healun.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120773PMC
September 2018

Fungal Infections Complicating Lung Transplantation.

Semin Respir Crit Care Med 2018 04 26;39(2):227-254. Epub 2018 Mar 26.

Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California.

Lung transplantation is an increasingly utilized modality for treating advanced lung disease. However, lung transplant recipients (LTRs) experience high rates of infection-related mortality and, compared with other solid organ transplant recipients, are at increased risk of infectious complications given the intensity of immunosuppression employed, the presence of airway abnormalities after surgery and exposure of the allograft to the environment. Fungal infections, particularly mold infections, are problematic after transplantation as they are often associated with limited treatment options and poor outcomes. We describe the non- fungal infections occurring in LTRs, including their epidemiology, clinical features, and treatment.
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http://dx.doi.org/10.1055/s-0037-1617443DOI Listing
April 2018

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies.

Semin Respir Crit Care Med 2018 04 26;39(2):155-171. Epub 2018 Mar 26.

Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California.

Lung transplantation has become an established therapeutic option for a variety of end-stage lung diseases. Technical advances in graft procurement, implantation, perioperative care, immunosuppression, and posttransplant medical management have led to significant improvements in 1-year survival, but outcomes after the first year have improved minimally over the last two decades. The main limitation to better long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD manifestations, risk factors, and mechanisms is rapidly evolving. Recognition of different CLAD phenotypes (e.g., bronchiolitis obliterans syndrome and restrictive allograft syndrome) and the unique pathogenic mechanisms will be important for developing novel therapies. In addition to alloimmune-mediated rejection, we now recognize the importance of alloimmune-independent mechanisms of injury to the allograft. CLAD is the consequence of dysregulated repair of allograft injury. Unfortunately, currently available therapies for CLAD are usually not effective. However, the advances in knowledge, reviewed in this manuscript, should lead to novel strategies for CLAD prevention and treatment, as well as improvement in long-term outcomes after lung transplantation. We provide an overview of the evolving terminology related to CLAD, its varying clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential treatments.
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http://dx.doi.org/10.1055/s-0037-1618567DOI Listing
April 2018

Pulmonary Allograft Versus Host Disease.

Transplant Direct 2017 Dec 20;3(12):e333. Epub 2017 Nov 20.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1097/TXD.0000000000000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828692PMC
December 2017

The Impact of Allograft CXCL9 during Respiratory Infection on the Risk of Chronic Lung Allograft Dysfunction.

OBM Transplant 2018 30;2(4). Epub 2018 Nov 30.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA.

Background: The long term clinical significance of respiratory infections after lung transplantation remains uncertain.

Methods: In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between respiratory infection and chronic lung allograft dysfunction (CLAD). We furthermore hypothesized that bronchoalveolar lavage fluid (BALF) CXCL9 concentrations are augmented during respiratory infections, and that episodes of infection with elevated BALF CXCL9 are associated with greater CLAD risk.

Results: In univariable and multivariable models adjusted for other histopathologic injury patterns, respiratory infection, regardless of the causative organism, was a strong predictor of CLAD development (adjusted HR 1.8 95% CI 1.3-2.6). Elevated BALF CXCL9 concentrations during respiratory infections markedly increased CLAD risk in a dose-response manner. An episode of respiratory infection with CXCL9 concentrations greater than the 25, 50, and 75 percentile had adjusted HRs for CLAD of 1.8 (95% CI 1.1-2.8), 2.4 (95% CI 1.4-4.0) and 4.4 (95% CI 2.4-8.0), respectively.

Conclusions: Thus, we demonstrate that respiratory infections, regardless of the causative organism, are strong predictors of CLAD development. We furthermore demonstrate for the first time, the prognostic importance of BALF CXCL9 concentrations during respiratory infections on the risk of subsequent CLAD development.
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http://dx.doi.org/10.21926/obm.transplant.1804029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693350PMC
November 2018

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft.

Transplantation 2018 06;102(6):986-993

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.

Background: Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.

Methods: We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant.

Results: Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD.

Conclusions: Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD.
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http://dx.doi.org/10.1097/TP.0000000000002058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962368PMC
June 2018

Host-Pathogen Interactions and Chronic Lung Allograft Dysfunction.

Ann Am Thorac Soc 2017 Sep;14(Supplement_3):S242-S246

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, California; and.

Lung transplantation is now considered to be a therapeutic option for patients with advanced-stage lung diseases. Unfortunately, due to post-transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Infections (e.g., bacterial, viral, and fungal) in the immunosuppressed lung transplant recipient are a common cause of mortality post transplant. Infections have more recently been explored as factors contributing to the risk of chronic lung allograft dysfunction (CLAD). Each major class of infection-(1) bacterial (Staphylococcus aureus and Pseudomonas aeruginosa); (2) viral (cytomegalovirus and community-acquired respiratory viruses); and (3) fungal (Aspergillus)-has been associated with the development of CLAD. Mechanistically, the microbe seems to be interacting with the allograft cells, stimulating the induction of chemokines, which recruit recipient leukocytes to the graft. The recipient leukocyte interactions with the microbe further up-regulate chemokines, amplifying the influx of allograft-infiltrating mononuclear cells. These events can promote recipient leukocytes to interact with the allograft, triggering an alloresponse and graft dysfunction. Overall, interactions between the microbe-allograft-host immune system alters chemokine production, which, in part, plays a role in the pathobiology of CLAD and mortality due to CLAD.
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http://dx.doi.org/10.1513/AnnalsATS.201606-464MGDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711338PMC
September 2017

The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation.

PLoS One 2017 7;12(7):e0180281. Epub 2017 Jul 7.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Rationale: Since the pathogenesis of chronic lung allograft dysfunction (CLAD) remains poorly defined with no known effective therapies, the identification and study of key events which increase CLAD risk is a critical step towards improving outcomes. We hypothesized that bronchoalveolar lavage fluid (BALF) CXCR3 ligand concentrations would be augmented during organizing pneumonia (OP) and that episodes of OP with marked chemokine elevations would be associated with significantly higher CLAD risk.

Methods: All transbronchial biopsies (TBBX) from patients who received lung transplantation between 2000 to 2010 were reviewed. BALF concentrations of the CXCR3 ligands (CXCL9, CXCL10 and CXCL11) were compared between episodes of OP and "healthy" biopsies using linear mixed-effects models. The association between CXCR3 ligand concentrations during OP and CLAD risk was evaluated using proportional hazards models with time-dependent covariates.

Results: There were 1894 bronchoscopies with TBBX evaluated from 441 lung transplant recipients with 169 (9%) episodes of OP and 907 (49%) non-OP histopathologic injuries. 62 (37%) episodes of OP were observed during routine surveillance bronchoscopy. Eight hundred thirty-eight (44%) TBBXs had no histopathology and were classified as "healthy" biopsies. There were marked elevations in BALF CXCR3 ligand concentrations during OP compared with "healthy" biopsies. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0-2.3), 1.9 (95% CI 1.2-2.8) and 2.2 (95% CI 1.4-3.4), respectively.

Conclusions: This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation, as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180281PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501470PMC
September 2017

The Prognostic Importance of Bronchoalveolar Lavage Fluid CXCL9 During Minimal Acute Rejection on the Risk of Chronic Lung Allograft Dysfunction.

Am J Transplant 2018 01 2;18(1):136-144. Epub 2017 Aug 2.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remain controversial. In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using bronchoalveolar lavage (BAL) CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose-response manner. Minimal AR with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had adjusted hazard ratios (HRs) for CLAD of 1.1 (95% confidence interval [CI] 0.8-1.6), 1.6 (95% CI 1.1-2.3), and 2.2 (95% CI 1.4-3.4), respectively. Thus we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development.
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http://dx.doi.org/10.1111/ajt.14397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739954PMC
January 2018

Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction.

J Clin Invest 2017 Jun 1;127(6):2022-2029. Epub 2017 Jun 1.

Inflammasomes are high-molecular-weight cytosolic complexes that mediate the activation of caspases. There are many inflammasomes, and each is influenced by a unique pattern-recognition receptor response. Two signals are typically involved in the inflammasome pathways. Signal one involves recognition of pathogen-associated molecular patterns (PAMPs), such as LPS or other colonizing/invading microbes, that interact with TLRs, which induce the downstream production of pro-IL-1β. This is followed by signal two, which involves recognition of PAMPs or damage-associated molecular patterns (DAMPs), such as uric acid or ATP, via NLRP3, which leads to caspase-1-dependent cleavage of pro-IL-1β to active IL-1β and pyroptosis. Ultimately, these two signals cause the release of multiple proinflammatory cytokines. Both PAMPs and DAMPs can be liberated by early insults to the allograft, including ischemia/reperfusion injury, infections, and rejection. The consequence of inflammasome activation and IL-1 expression is the upregulation of adhesion molecules and chemokines, which leads to allograft neutrophil sequestration, mononuclear phagocyte recruitment, and T cell activation, all of which are key steps in the continuum from allograft insult to chronic allograft dysfunction.
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http://dx.doi.org/10.1172/JCI93537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451233PMC
June 2017

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction.

PLoS One 2017 19;12(1):e0169894. Epub 2017 Jan 19.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.

Background: Chronic Lung Allograft Dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Although CLAD is usually not responsive to treatment, earlier identification may improve treatment prospects.

Methods: In a nested case control study, 1-year post transplant surveillance bronchoalveolar lavage (BAL) fluid samples were obtained from incipient CLAD (n = 9) and CLAD free (n = 8) lung transplant recipients. Incipient CLAD cases were diagnosed with CLAD within 2 years, while controls were free from CLAD for at least 4 years following bronchoscopy. Transcription profiles in the BAL cell pellets were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression analysis, based on an absolute fold change (incipient CLAD vs no CLAD) >2.0 and an unadjusted p-value ≤0.05, generated a candidate list containing 55 differentially expressed probe sets (51 up-regulated, 4 down-regulated).

Results: The cell pellets in incipient CLAD cases were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation and proliferation of cytotoxic lymphocytes (CD8+ T-cells and natural killer cells). Both hierarchical clustering and a supervised machine learning tool were able to correctly categorize most samples (82.3% and 94.1% respectively) into incipient CLAD and CLAD-free categories.

Conclusions: These findings suggest that a pathobiology, similar to AR, precedes a clinical diagnosis of CLAD. A larger prospective investigation of the BAL cell pellet transcriptome as a biomarker for CLAD risk stratification is warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169894PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245825PMC
August 2017

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.

Elife 2016 12 9;5. Epub 2016 Dec 9.

Merck KGaA, Darmstadt, Germany.

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.
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http://dx.doi.org/10.7554/eLife.20722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224920PMC
December 2016

Impact of Allograft Injury Time of Onset on the Development of Chronic Lung Allograft Dysfunction After Lung Transplantation.

Am J Transplant 2017 05 31;17(5):1294-1303. Epub 2016 Oct 31.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

The impact of allograft injury time of onset on the risk of chronic lung allograft dysfunction (CLAD) remains unknown. We hypothesized that episodes of late-onset (≥6 months) allograft injury would produce an augmented CXCR3/ligand immune response, leading to increased CLAD. In a retrospective single-center study, 1894 transbronchial biopsy samples from 441 lung transplant recipients were reviewed for the presence of acute rejection (AR), lymphocytic bronchiolitis (LB), diffuse alveolar damage (DAD), and organizing pneumonia (OP). The association between the time of onset of each injury pattern and CLAD was assessed by using multivariable Cox models with time-dependent covariates. Bronchoalveolar lavage (BAL) CXCR3 ligand concentrations were compared between early- and late-onset injury patterns using linear mixed-effects models. Late-onset DAD and OP were strongly associated with CLAD: adjusted hazard ratio 2.8 (95% confidence interval 1.5-5.3) and 2.0 (1.1-3.4), respectively. The early-onset form of these injury patterns did not increase CLAD risk. Late-onset LB and acute rejection (AR) predicted CLAD in univariable models but lost significance after multivariable adjustment for late DAD and OP. AR was the only early-onset injury pattern associated with CLAD development. Elevated BAL CXCR3 ligand concentrations during late-onset allograft injury parallel the increase in CLAD risk and support our hypothesis that late allograft injuries result in a more profound CXCR3/ligand immune response.
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http://dx.doi.org/10.1111/ajt.14066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368037PMC
May 2017