Molecular assessment of rejection and injury in lung transplant biopsies

Kieran M. Halloran, Michael D. Parkes, Jessica Chang, Irina L. Timofte, Gregory I. Snell, Glen P. Westall, Ramsey Hachem, Daniel Kreisel, Elbert Trulock, Antoine Roux, Stephen Juvet, Shaf Keshavjee, Peter Jaksch, Walter Klepetko, Philip F. Halloran

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

BACKGROUND: Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. METHODS: We prospectively studied whether microarray assessment of single TBB pieces could identify disease states and reduce the amount of tissue required for diagnosis. By following strategies successful for heart transplants, we used expression of rejection-associated transcripts (annotated in kidney transplant biopsies) in unsupervised machine learning to identify disease states. RESULTS: All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis, we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified 4 idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal; T-cell‒mediated rejection (TCMR; T-cell transcripts); antibody-mediated rejection (ABMR)-like (endothelial transcripts); and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population. CONCLUSIONS: Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or 3 pieces for each TBB will probably be needed to offset sampling variance.

Original languageEnglish
Pages (from-to)504-513
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume38
Issue number5
DOIs
StatePublished - May 2019

Keywords

  • T-cell‒mediated rejection
  • antibody-mediated rejection
  • gene expression
  • microarray
  • surfactant

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    Halloran, K. M., Parkes, M. D., Chang, J., Timofte, I. L., Snell, G. I., Westall, G. P., Hachem, R., Kreisel, D., Trulock, E., Roux, A., Juvet, S., Keshavjee, S., Jaksch, P., Klepetko, W., & Halloran, P. F. (2019). Molecular assessment of rejection and injury in lung transplant biopsies. Journal of Heart and Lung Transplantation, 38(5), 504-513. https://doi.org/10.1016/j.healun.2019.01.1317