Molecular T-cell‒mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss

Abstract

BACKGROUND: We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies, identifying Tcell-mediated rejection (TCMR) on the basis of the expression of rejection-associated transcripts, but the relationship of rejection to graft loss is unknown. This study aimed to develop molecular assessments for TBBs and mucosal biopsies and to establish the impact of molecular TCMR on graft survival. METHODS: We used microarrays and machine learning to assign TCMR scores to an expanded cohort of 457 TBBs (367 high surfactant plus 90 low surfactant) and 314 mucosal biopsies. We tested the score agreement between TBB−TBB, mucosal−mucosal, and TBB−mucosal biopsy pairs in the same patient. We also assessed the association of molecular TCMR scores with graft loss (death or retransplantation) and compared it with the prognostic associations for histology and donor-specific antibodies. RESULTS: The molecular TCMR scores assigned in all the TBBs performed similarly to those in high-surfactant TBBs, indicating that variation in alveolation in TBBs does not prevent the detection of TCMR. Mucosal biopsy pieces showed less piece-to-piece variation than TBBs. TCMR scores in TBBs agreed with those in mucosal biopsies. In both TBBs and mucosal biopsies,

Clinical Validation of a Plasma Donor-derived Cell-free DNA Assay to Detect Allograft Rejection and Injury in Lung Transplant

“… 36 It is possible that misclassification between diagnostic cohorts could have influenced results of our analyses. Future studies incorporating outcome measures may shed additional light on the relationship of dd-cfDNA, AR and graft injury, and histopathology, not to mention more speculative markers such as intragraft gene expression profile signatures 37 and epigenetic signatures such as DNA methylation. 38 Nevertheless, our study design and sample size permits insights regarding dd-cfDNA fractions and performance of a clinical assay across diverse types of LT allograft injury and health.…”

Acute Rejection in the Modern Lung Transplant Era

“…[126][127][128] A recent study showed that microarray analysis of rejection-associated transcripts from single-piece transbronchial biopsies is correlated with rejection histology. 129,130 It is still unclear whether these ancillary techniques can improve the diagnostic accuracy of standard histology in LTx but results are promising.…”

Novel biomarkers of chronic lung allograft dysfunction: is there anything reliable?

“…One example includes the presence of acute fibrinous and organizing pneumonia on late (>3 months after the transplantation) transbronchial biopsies, which occurred in 6% of transplant patients, and which proved to be a strong risk factor for CLAD, specifically RAS ]. Molecular gene expression signatures previously applied in other solid organ transplants could also be of considerable interest as a specific T-cell signature could be identified in transbronchial and endobronchial biopsies, which was associated with graft loss [32]. Other relevant rejection signatures could also be identified including a normal, antibody-mediated rejection and injury signature of which the prognostic importance is still unknown [33].…”