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

Shino, Michael Y.; Weigt, S. Samuel; Li, Ning; Palchevskiy, Vyacheslav; Derhovanessian, Ariss; Saggar, Rajan; Sayah, David M.; Huynh, Richard; Gregson, Aric L.; Fishbein, Michael C.; Ardehali, A.; Ross, David J.; Lynch, Joseph P.; Elashoff, Robert M.; Belperio, John A.

doi:10.1371/journal.pone.0180281

Cited by 23 publications

(20 citation statements)

References 31 publications

(31 reference statements)

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“…Attempts were made to identify markers from BAL fluid to detect allograft rejection [ 12 ]; however, no marker has been identified that has the predictive power [ 13 ]. From previous studies, a pro-inflammatory cytokine—CXCL10—in BAL was reported to be associated with the risk factor of CLAD development [ 14 ]. A study by Yang et al reported using cfDNA and CXCL10 derived from BAL to detect and distinguish subphenotypes of CLAD and to predict lung transplant survival [ 15 ].…”

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confidence: 99%

New Clue: Prediction from Cell-Free DNA

Sanders

2020

JCM

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The main challenge for a positive long-term outcome in lung transplantation is the lack of early detection for chronic lung allograft dysfunction (CLAD). With advancements in technology, an increasing number of studies demonstrate that cell-free DNA (cfDNA) in body fluids could be used as a marker for disease diagnosis, prognosis or monitoring response to treatment. A previous report from this journal found the joint assessment of cfDNA and CXCL10 from brochoalveolar lavage (BAL) could determine the subphenotypes of CLAD and predict lung transplant survival. This is an exciting attempt in monitoring the progress for lung transplant recipients. More studies and better understanding of cfDNA are needed to develop an accessible and reliable biomarker to monitor the progress of CLAD to improve the long-term survival for lung transplant recipients.

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confidence: 99%

New Clue: Prediction from Cell-Free DNA

Sanders

2020

JCM

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“…149 As previously noted, the major risk factor for RAS is DAD, 114,115 and possibly OP as well. 130 Thus, we infer that BOS is preceded by injury to the small airways, whereas RAS follows an injury that may involve the small airways as well, but also extends distally to the alveoli.…”

Section: Mechanisms Of Clad Pathogenesis Injury and Dysregulated Repamentioning

confidence: 83%

“…115 Furthermore, BAL fluid concentrations of these chemokines are increased during injury, and the levels associate with the subsequent development of CLAD. 115,[128][129][130] CXCR3 chemokine ligands are also increased during community-acquired respiratory viral infection, and high levels predicted worse allograft function 6 months after recovery from the infection. 131 These studies suggest that CXCR3/ligand biology during allograft injury may set up the scenario for progression to CLAD by recruiting cytotoxic lymphocytes to the graft.…”

Section: Mechanisms Of Clad Pathogenesis Injury and Dysregulated Repamentioning

confidence: 99%

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

Amubieya

Ramsey

Derhovanessian

et al. 2018

Semin Respir Crit Care Med

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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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“…This finding is corroborated by previous work showing that protein concentrations of the interferon gamma–inducible CXCR3-binding chemokines in the BAL fluid are associated with A-grade ACR and other lung injury patterns, as well as with CLAD. 25 , 26 , 27 Finally, enrichment for pathways related to cell adhesion, NK cell–mediated cytotoxicity, and allograft rejection add additional support of the biological relevance of BAL CP gene expression during A-grade ACR.…”

Section: Discussionmentioning

confidence: 94%

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

Weigt

Wang

Palchevskiy

et al. 2019

The Journal of Heart and Lung Transplantation

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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 Benjaminiadjusted 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).

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

Cited by 23 publications

References 31 publications

New Clue: Prediction from Cell-Free DNA

New Clue: Prediction from Cell-Free DNA

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

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

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