Proteoforms in Peripheral Blood Mononuclear Cells as Novel Rejection Biomarkers in Liver Transplant Recipients
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Date
2017
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Volume Title
Publisher
American Journal of Transplantation
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Abstract
Biomarker profiles diagnostic of acute rejection (AR) in liver transplant (LT) recipients could enhance the diagnosis and management of recipients. Our aim was to identify diagnostic proteoform-resolved signatures for AR in PBMC, using a novel top down proteomics methodology. We processed viable and non-viable PBMC lysates from 24 non-HCV+ LT recipients (age 60±15.6 years, 66.6% male, mean 3.7±3.3 year from LT) undergoing liver biopsy by molecular weight based fractionation and analyzed them by top-down proteomics in 3 steps: 1) Nanocapillary liquid chromatography coupled with high-resolution tandem mass spectrometry, 2) database searching to identify and characterize proteoforms, 3) data processing through a linear hierarchical model matching the study design to quantify proteoform fold changes in AR vs. Tx (normal liver function) vs. ADNR (acute dysfunction without rejection).
Differentially abundant proteoforms were seen in patients with AR vs. TX and AR vs. ADNR, suggesting a distinct proteoform signature of AR in LT recipients. This was most evident in the viable cell preparations. Mapping analysis of these proteins back to genes through PANTHER and GO revealed multiple signaling pathways, including inflammation mediated by cytokines and chemokines. Larger studies are needed to validate these signatures and test their predictive value for use in clinical management.
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Keywords
Top-down proteomics, Translational proteomics, Mass spectrometry, Proteoform, Transplantation, Liver Transplantation, Transplant Rejection, Biomarkers
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Forthcoming
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Forthcoming
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