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JCI Insight. 2018 Jan 25;3(2). pii: 95659. doi: 10.1172/jci.insight.95659. eCollection 2018 Jan 25.

Inflammatory macrophage-associated 3-gene signature predicts subclinical allograft injury and graft survival.

Author information

1
Stanford Institute for Immunity, Transplantation and Infection and.
2
Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA.
3
Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.
4
Department of Immunology, Technion-Israel Institute of Technology, Haifa, Israel.
5
Division of Nephrology, Department of Medicine, Stanford University, Stanford, California, USA.

Abstract

Late allograft failure is characterized by cumulative subclinical insults manifesting over many years. Although immunomodulatory therapies targeting host T cells have improved short-term survival rates, rates of chronic allograft loss remain high. We hypothesized that other immune cell types may drive subclinical injury, ultimately leading to graft failure. We collected whole-genome transcriptome profiles from 15 independent cohorts composed of 1,697 biopsy samples to assess the association of an inflammatory macrophage polarization-specific gene signature with subclinical injury. We applied penalized regression to a subset of the data sets and identified a 3-gene inflammatory macrophage-derived signature. We validated discriminatory power of the 3-gene signature in 3 independent renal transplant data sets with mean AUC of 0.91. In a longitudinal cohort, the 3-gene signature strongly correlated with extent of injury and accurately predicted progression of subclinical injury 18 months before clinical manifestation. The 3-gene signature also stratified patients at high risk of graft failure as soon as 15 days after biopsy. We found that the 3-gene signature also distinguished acute rejection (AR) accurately in 3 heart transplant data sets but not in lung transplant. Overall, we identified a parsimonious signature capable of diagnosing AR, recognizing subclinical injury, and risk-stratifying renal transplant patients. Our results strongly suggest that inflammatory macrophages may be a viable therapeutic target to improve long-term outcomes for organ transplantation patients.

KEYWORDS:

Immunology; Macrophages; Organ transplantation; Transplantation

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