Observational Study

. 2025 Aug 1;109(8):1367-1382.

doi: 10.1097/TP.0000000000005269. Epub 2025 Jan 9.

Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study

Katelynn S Madill-Thomsen¹, Patrick T Gauthier¹, Marwan Abouljoud², Chandra Bhati³, David Bruno⁴, Michał Ciszek⁵, Magdalena Durlik⁶, Sandy Feng⁷, Bartosz Foroncewicz⁵, Michał Grąt⁸, Krzysztof Jurczyk⁹, Josh Levitsky¹⁰, Geoff McCaughan¹¹, Daniel Maluf⁴, Aldo Montano-Loza¹², Dilip Moonka², Krzysztof Mucha⁵, Marek Myślak⁹, Agnieszka Perkowska-Ptasińska¹³, Grzegorz Piecha¹⁴, Trevor Reichman³, Olga Tronina⁸, Marta Wawrzynowicz-Syczewska⁹, Samir Zeair⁹, Philip F Halloran¹

Affiliations

¹ Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.
² Department of Surgery, Henry Ford Hospital, Virginia Commonwealth University, Richmond, VA.
³ Virginia Commonwealth University, Richmond, VA.
⁴ Department of Surgery, University of Maryland, Baltimore, MD.
⁵ Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁶ Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁷ Department of Surgery, University of California San Francisco, San Francisco, CA.
⁸ Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
⁹ Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.
¹⁰ Department of Medicine, Northwestern University, Chicago, IL.
¹¹ Australian National Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia.
¹² Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹³ Department of Pathology, Medical University of Warsaw, Warsaw, Poland.
¹⁴ Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland.

PMID: 39780312
DOI: 10.1097/TP.0000000000005269

Observational Study

Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study

Katelynn S Madill-Thomsen et al. Transplantation. 2025.

. 2025 Aug 1;109(8):1367-1382.

doi: 10.1097/TP.0000000000005269. Epub 2025 Jan 9.

Authors

Affiliations

¹ Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.
² Department of Surgery, Henry Ford Hospital, Virginia Commonwealth University, Richmond, VA.
³ Virginia Commonwealth University, Richmond, VA.
⁴ Department of Surgery, University of Maryland, Baltimore, MD.
⁵ Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁶ Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁷ Department of Surgery, University of California San Francisco, San Francisco, CA.
⁸ Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
⁹ Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.
¹⁰ Department of Medicine, Northwestern University, Chicago, IL.
¹¹ Australian National Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia.
¹² Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹³ Department of Pathology, Medical University of Warsaw, Warsaw, Poland.
¹⁴ Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland.

PMID: 39780312
DOI: 10.1097/TP.0000000000005269

Abstract

Background: Initial analysis of liver transplant biopsies in the INTERLIVER study ( ClinicalTrials.gov ; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population.

Methods: We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers.

Results: The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities.

Conclusions: Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.

Trial registration: ClinicalTrials.gov NCT03193151 NCT05021484.

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Conflict of interest statement

P.F.H. holds shares in Transcriptome Sciences Inc, 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.H. is a consultant to Natera Inc and Argenx BV. The other authors declare no conflicts of interest.

References

1. Lucey MR, Furuya KN, Foley DP. Liver transplantation. N Engl J Med. 2023;389:1888–1900.
1. McCaughan GW, Gorrell MD, Bishop GA, et al. Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance. Immunol Rev. 2000;174:172–191.
1. Neuberger J. An update on liver transplantation: a critical review. J Autoimmun. 2016;66:51–59.
1. Zarrinpar A, Busuttil RW. Liver transplantation: past, present and future. Nat Rev Gastroenterol Hepatol. 2013;10:434–440.
1. Wadstrom J, Ericzon BG, Halloran PF, et al. Advancing transplantation: new questions, new possibilities in kidney and liver transplantation. Transplantation. 2017;101(Suppl 2S):S1–S41.

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Grants and funding

This research has been principally supported by grants from Genome Canada, Canada Foundation for Innovation, the University of Alberta Hospital Foundation, the Alberta Ministry of Advanced Education and Technology, the Mendez National Institute of Transplantation Foundation, and Industrial Research Assistance Program. Partial support was also provided by funding from a licensing agreement with the One Lambda division of Thermo Fisher. Dr. Halloran held a Canada Research Chair in Transplant Immunology until 2008 and currently holds the Muttart Chair in Clinical Immunology.

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Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study

Affiliations

Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical