The common rejection module in chronic rejection post lung transplantation

PLoS One. 2018 Oct 5;13(10):e0205107. doi: 10.1371/journal.pone.0205107. eCollection 2018.

Abstract

Rationale: Recent studies suggest that similar injury mechanisms are in place across different solid organ transplants, resulting in the identification of a common rejection module (CRM), consisting of 11 genes that are overexpressed during acute and, to a lesser extent, chronic allograft rejection.

Objectives: We wanted to evaluate the usefulness of the CRM module in identifying acute rejection (AR) and different phenotypes of chronic lung transplant rejection (CLAD), i.e., bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), using transbronchial brushings, broncho-alveolar lavage (BAL) samples, and explant tissue.

Methods: Gene expression measurements for the 11 CRM genes (CD6, TAP1, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, and BASP1) were performed via qRT-PCR in 14 transbronchial brushings (AR, n = 4; no AR, n = 10), 32 BAL samples (stable, n = 13; AR, n = 8; BOS, n = 9; RAS, n = 10), and 44 tissue specimens (unused donor lungs, n = 15; BOS, n = 13; RAS, n = 16). A geometric mean score was calculated to quantitate overall burden of immune injury and a new computational model was built for the most significant genes in lung transplant injury.

Results: Acute rejection showed a significant difference in almost every gene analysed, validating previous observations from microarray analysis. RAS tissue demonstrated a higher geometric mean score (6.35) compared to donor tissue (4.09, p = 0.018). Analysis of individual CRM genes showed an increased expression of ISG20, CXCL10 and CXCL9 in RAS. In BAL samples, no differences were detected in gene expression or geometric mean scores between the various groups (stable, 5.15; AR, 5.81; BOS, 5.62; RAS, 7.31). A newly modelled 2-gene tissue CRM score did not demonstrate any difference between BOS and RAS (p>0.05). However, the model was able to discriminate RAS from BOS tissue (AUC = 0.75, 95% CI = 0.55-0.94, p = 0.025).

Conclusion: Transcriptional tissue analysis for CRM genes in CLAD can identify acute rejection and distinguish RAS from BOS. The immune activation in RAS seems similar to acute rejection after kidney/liver/heart transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allografts / metabolism
  • Biomarkers / metabolism
  • Bronchoalveolar Lavage
  • Chronic Disease
  • Cohort Studies
  • Computer Simulation
  • Female
  • Gene Expression
  • Graft Rejection / metabolism*
  • Humans
  • Lung / metabolism
  • Lung / surgery
  • Lung Transplantation*
  • Male
  • Middle Aged
  • Transcriptome
  • Transplantation, Homologous
  • Young Adult

Substances

  • Biomarkers

Grants and funding

Authors of this work were supported by several funding resources. RV and SEV are senior clinical research fellows sponsored by Reaseach Foundation - Flanders (FWO: 12G8715N and 1500617N). RV is supported by UZ Leuven (STG/15/023). GMV and BMV are supported by KU Leuven research funding C24/15/030. MMS and TKS have research support from the NIH (NIAID and NIDDK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.