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

Autor:	Gauthier PT; University of Alberta, Edmonton, Alberta, Canada., Mackova M; University of Alberta, Edmonton, Alberta, Canada., Hirji A; University of Alberta, Edmonton, Alberta, Canada., Weinkauf J; University of Alberta, Edmonton, Alberta, Canada., Timofte IL; UT Southwestern Medical Center, Dallas, Texas, USA., Snell GI; Alfred Hospital Lung Transplant Service, Melbourne, Victoria, Australia., Westall GP; Alfred Hospital Lung Transplant Service, Melbourne, Victoria, Australia., Havlin J; University Hospital Motol, Prague, Czech Republic., Lischke R; University Hospital Motol, Prague, Czech Republic., Zajacová A; University Hospital Motol, Prague, Czech Republic., Simonek J; University Hospital Motol, Prague, Czech Republic., Hachem R; Washington University in St Louis, St. Louis, Missouri, USA., Kreisel D; Washington University in St Louis, St. Louis, Missouri, USA., Levine D; Stanford University, Stanford, California, USA., Kubisa B; Pomeranian Medical University of Szczecin, Szczecin, Poland., Piotrowska M; Pomeranian Medical University of Szczecin, Szczecin, Poland., Juvet S; Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada., Keshavjee S; Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada., Jaksch P; Medical University of Vienna, Vienna, Austria., Klepetko W; Medical University of Vienna, Vienna, Austria., Halloran K; University of Alberta, Edmonton, Alberta, Canada., Halloran PF; University of Alberta, Edmonton, Alberta, Canada. Electronic address: phallora@ualberta.ca.
Jazyk:	angličtina
Zdroj:	American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Am J Transplant] 2023 Dec; Vol. 23 (12), pp. 1922-1938. Date of Electronic Publication: 2023 Jun 07.
DOI:	10.1016/j.ajt.2023.06.003
Abstrakt:	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. Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P F Halloran reports financial support was provided by Thermo Fisher Scientific. P F Halloran reports financial support was provided by Natera Inc. P F Halloran reports a relationship with Natera, Inc. that includes: consulting or advisory. Disclosure P F Halloran holds shares in Transcriptome Sciences Inc (TSI), a University of Alberta research company dedicated to developing molecular diagnostics, supported in part by a licensing agreement between TSI and Thermo Fisher Scientific, and by a research grant from Natera Inc. P.F. Halloran is a consultant to Natera Inc. The other authors have nothing to disclose. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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