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

Weigt, S. Samuel; Wang, Xiaoyan; Palchevskiy, Vyacheslav; Patel, Neil; Derhovanessian, Ariss; Shino, Michael Y.; Sayah, David M.; Gregson, Aric L.; Lynch, Joseph P.; Saggar, Rajan; Ross, David J.; Ardehali, A.; Elashoff, David; Belperio, John A.

doi:10.1513/annalsats.201608-618mg

Cited by 13 publications

(20 citation statements)

References 21 publications

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“…BALF cell pellet and exosome transcriptome in patients with AR and CR after LTx have demonstrated molecular signatures primarily involving innate and adaptive cytotoxic immune responses. 19 Recently, we demonstrated that exosomes isolated from sera and BALF of LTxRs diagnosed with AR or CR contains not only DSA but also the lung SAgs Col-V and Kα1T. These results suggest that exosomes induced during rejection of the transplanted lungs can induce immune responses, thereby increasing the risk of development of BOS.…”

Section: Discussionmentioning

confidence: 90%

A novel mechanism for immune regulation after human lung transplantation

Mohanakumar

Sharma

Bansal

et al. 2019

The Journal of Thoracic and Cardiovascular Surgery

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Objective: Lung transplantation is therapeutic for end-stage lung disease, but survival is limited due to bronchiolitis obliterans syndrome and restrictive chronic lung allograft dysfunction. We sought a common denominator in lung transplant recipients, analyzing risk factors that trigger immune responses that lead to bronchiolitis obliterans syndrome. Methods:We collected blood from patients who underwent lung transplant at our institution. Exosomes were isolated from the sera of recipients with risk factors for chronic rejection and from stable recipients. Exosomes were analyzed with western blot, using antibodies to lung self-antigens K alpha 1 tubulin and collagen-V, costimulatory molecules (costimulatory molecule 80, costimulatory molecule 86), transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells, hypoxia-inducible factor 1a, Class II Major Histocompatibility Complex Transactivator), and 20S proteasome.

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Section: Discussionmentioning

confidence: 90%

A novel mechanism for immune regulation after human lung transplantation

Mohanakumar

Sharma

Bansal

et al. 2019

The Journal of Thoracic and Cardiovascular Surgery

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“… 23 We have also previously shown that BAL CP gene expression of CD8 and LCK is associated with the development of CLAD. 24 In addition, the cytokine–cytokine receptor interaction pathway was enriched 6.5-fold and included CXCR3 and interferon gamma. 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.…”

Section: Discussionmentioning

confidence: 99%

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 cell pellets from cases that developed CLAD were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation, and proliferation of cytotoxic lymphocytes (CD8 þ T cells and natural killer cells). 218 Given the similarity of this pathobiology to what is seen with ACR, 219,220 these findings suggest a potential to intervene with immune suppression, prior to our current ability to make a CLAD diagnosis. However, this hypothesis requires testing and validation in future clinical trials.…”

Section: Treatment Of Cladmentioning

confidence: 94%

“…Recently, we studied BAL cell pellet gene expression in patients who developed CLAD within 2 years as compared with those who remained CLAD free in the long term. 218 All patients had a TBB negative for AR at the time of BAL cell pellet acquisition. The cell pellets from cases that developed CLAD were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation, and proliferation of cytotoxic lymphocytes (CD8 þ T cells and natural killer cells).…”

Section: Treatment Of Cladmentioning

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

Abstract: Background

Cited by 13 publications

References 21 publications

A novel mechanism for immune regulation after human lung transplantation

A novel mechanism for immune regulation after human lung transplantation

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

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

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