Proteoforms in Peripheral Blood Mononuclear Cells as Novel Rejection Biomarkers in Liver Transplant Recipients
Open accessAbstract
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.
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AR and ADNR phenotypes were diagnosed by needle biopsy, and TX by clinical and laboratory criteria, as previously described.
“The AR and ADNR phenotypes were diagnosed by needle biopsy, and TX by clinical and laboratory criteria, as previously described (31–34).”
From The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells (2022) · cites this paper as [31]
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- Authors
- Toby, T. K., Abecassis, M., Kim, K., Thomas, P. M., Fellers, R. T., LeDuc, R. D., Kelleher, N. L., Demetris, J., & Levitsky, J.
- Affiliations
- Northwestern University (US)
- University of Pittsburgh (US)
- Corresponding author
- Levitsky, J.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 17
- Issue
- 9
- Pages
- 2458-2467
- ISSN
- 1600-6135 (ISSN-L)
- PMC
- PMC5612406
- OpenAlex
- W2596316072
- Cited by
- 42
- References
- 31
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 2
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (P41 GM108569)
- National Institute of General Medical Sciences of the National Institutes of Health (T32GM105538)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- liver transplantation, acute rejection, proteoforms, peripheral blood mononuclear cells, top-down proteomics, rejection biomarkers, circulating immune cells, cytokines, chemokines, inflammatory signaling
- MeSH terms
- Female, Graft Rejection, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Prognosis, Biomarkers, Liver Transplantation, Protein Isoforms, Proteome, Databases, Protein, Proteomics
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