Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival
Tej D. Azad, … , Maarten Naesens, Purvesh Khatri
Tej D. Azad, … , Maarten Naesens, Purvesh Khatri
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e95659. https://doi.org/10.1172/jci.insight.95659.
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Research Article Immunology Transplantation

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

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.

Authors

Tej D. Azad, Michele Donato, Line Heylen, Andrew B. Liu, Shai S. Shen-Orr, Timothy E. Sweeney, Jonathan Scott Maltzman, Maarten Naesens, Purvesh Khatri

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Figure 3

M1 score is diagnostic and prognostic in longitudinally collected protocol biopsies from renal transplant patients.

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M1 score is diagnostic and prognostic in longitudinally collected protoc...
(A) M1 scores in renal biopsies from nonprogressors, progressors, and AR transplant patients in GSE25902. (B and C) Comparison of M1 scores (y axis) with Banff tubulitis (t-score) and interstitial inflammation (i-score) scores in renal transplant patients, respectively. (D and E) Comparison of M1 scores with ct-score and ci-score in STA renal transplant patients who did not have AR episodes in the first 2 years after transplant. (F) Change in M1 scores over time in STA renal transplant patients. Patients were divided into 2 groups: progressors (n = 12, CADI ≥ 6) and nonprogressors (n = 12, CADI < 6) 2 years after transplant. Protocol biopsies were obtained from each patient at 3 time points: the time of transplant, 6 months after transplant, and 24 months after transplant. Repeated-measures analysis of variance was used to analyze CRM scores between progressors and nonprogressors over the time points. The dotted blue line represents the mean M1 score in AR biopsies; solid red line represents the mean M1 score in STA biopsies. (G) Six-month protocol biopsy M1 scores were used to predict patients with severe histological damage ≥2 years after transplant. A JT trend test was used to compute P values for correlations between M1 scores and Banff t- and i-scores as well as ct- and ci-scores. Error bars indicate the standard error of the mean.