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Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients.

ABSTRACT: Acute cellular rejection (ACR) is a common complication in lung transplantation and associated with increased risk of chronic allograft dysfunction. MicroRNAs are critical controllers of cellular transcription whose expression can be altered in disease states. The purpose of this pilot study was to evaluate whether microRNA profiling of epithelial cells obtained from airway brushings can distinguish lung transplant patients with ACR from those without rejection. We studied 21 subjects (10 with ACR, 11 without ACR) and assessed the expression of over 700 microRNAs in their airway epithelium. We identified 117 differentially expressed microRNAs that robustly segregated the two groups, and were uniformly downregulated in patients with ACR. Leveraging experimentally verified microRNA targets, we systematically mapped pathways and processes regulated by ACR-induced microRNAs and noted enrichment of programs involved in development, proliferation, migration, and repair. Collectively, our study suggests that ACR is associated with a distinct epithelial microRNA signature that can provide insight into the pathogenesis of acute rejection and potentially serve as a sensitive, minimally invasive biomarker tool for diagnostic and prognostic stratification of lung transplant patients.

SUBMITTER: Gharib SA

PROVIDER: S-EPMC4914138 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNoninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection.MethodsThe Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use.ResultsThe GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively.ConclusionsWe identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

Project description:BackgroundAcute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients.MethodsThe cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant.ResultsIn analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60; P = 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (P = 0.32).ConclusionsThese results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.

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Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients.

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