Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies

Patrick T. Gauthier, Martina Mackova, Alim Hirji, Justin Weinkauf, Irina L. Timofte, Greg I. Snell, Glen P. Westall, Jan Havlin, Robert Lischke, Andrea Zajacová, Jan Simonek, Ramsey Hachem, Daniel Kreisel, Deborah Levine, Bartosz Kubisa, Maria Piotrowska, Stephen Juvet, Shaf Keshavjee, Peter Jaksch, Walter KlepetkoKieran Halloran, Philip F. Halloran

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.

Original languageEnglish
Pages (from-to)1922-1938
Number of pages17
JournalAmerican Journal of Transplantation
Issue number12
StatePublished - Dec 2023


  • CLAD
  • NK cells
  • NKRL
  • TBB
  • TCMR


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