Proteoforms in Peripheral Blood Mononuclear Cells as Novel Rejection Biomarkers in Liver Transplant Recipients

Biomarker profiles of acute rejection in liver transplant recipients could enhance the diagnosis and management of recipients. Our aim was to identify diagnostic proteoform signatures of acute rejection in circulating immune cells, using an emergent “top‐down” proteomics methodology. We prepared dif...

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Veröffentlicht in:American journal of transplantation 2017-09, Vol.17 (9), p.2458-2467
Hauptverfasser: Toby, T. K., Abecassis, M., Kim, K., Thomas, P. M., Fellers, R. T., LeDuc, R. D., Kelleher, N. L., Demetris, J., Levitsky, J.
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Sprache:eng
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Zusammenfassung:Biomarker profiles of acute rejection in liver transplant recipients could enhance the diagnosis and management of recipients. Our aim was to identify diagnostic proteoform signatures of acute rejection in circulating immune cells, using an emergent “top‐down” proteomics methodology. We prepared differentially processed and cryopreserved cell lysates from 26 nonviral liver transplant recipients by molecular weight–based fractionation and analyzed them by mass spectrometry of whole proteins in three steps: (i) Nanocapillary liquid chromatography coupled with high‐resolution tandem mass spectrometry; (ii) database searching to identify and characterize intact proteoforms; (iii) data processing through a hierarchical linear model matching the study design to quantify proteoform fold changes in patients with rejection versus normal liver function versus acute dysfunction without rejection. Differentially expressed proteoforms were seen in patients with rejection versus normal and nonspecific controls, most evidently in the cell preparations stored in traditional serum‐rich media. Mapping analysis of these proteins back to genes through gene ontology and pathway analysis tools revealed multiple signaling pathways, including inflammation mediated by cytokines and chemokines. Larger studies are needed to validate these novel rejection signatures and test their predictive value for use in clinical management. Distinct proteoforms are expressed in peripheral blood mononuclear cells of liver transplant recipients with acute rejection, and this supports top‐down proteomics as an approach to identify immune activation biomarkers for future clinical applications.
ISSN:1600-6135
1600-6143
DOI:10.1111/ajt.14359