Proteomics: Its Promise and Pitfalls in Shaping Precision Medicine in Solid Organ Transplantation

Abstract

Solid organ transplantation is an established treatment of choice for end-stage organ failure. However, all transplant patients are at risk of developing complications, including allograft rejection and death. Histological analysis of graft biopsy is still the gold standard for evaluation of allograft injury, but it is an invasive procedure and prone to sampling errors. The past decade has seen an increased number of efforts to develop minimally invasive procedures for monitoring allograft injury. Despite the recent progress, limitations such as the complexity of proteomics-based technology, the lack of standardization, and the heterogeneity of populations that have been included in different studies have hindered proteomic tools from reaching clinical transplantation. This review focuses on the role of proteomics-based platforms in biomarker discovery and validation in solid organ transplantation. We also emphasize the value of biomarkers that provide potential mechanistic insights into the pathophysiology of allograft injury, dysfunction, or rejection. Additionally, we forecast that the growth of publicly available data sets, combined with computational methods that effectively integrate them, will facilitate a generation of more informed hypotheses for potential subsequent evaluation in preclinical and clinical studies. Finally, we illustrate the value of combining data sets through the integration of 2 independent data sets that pinpointed hub proteins in antibodymediated rejection.

Mass spectrometry-based proteomics for advancing solid organ transplantation research

“…Such information could elucidate mechanisms underlying injury and rejection and lead to novel biomarkers and therapeutic strategies. However, technical, and economic challenges still prevent the transition of these new technologies from discovery to clinical applications ( 20 , 93 , 130 ).…”

“…In TDP, which is often coupled with LC, proteoforms are separated and directly ionized into mass spectrometers where the intact mass spectra (MS 1 ) are collected, and ions further fragmented (MS 2 ) for sequencing and PTM site identification (Figure 2B). Further advantages and limitations of TDP and BUP were reviewed elsewhere (20,82). TDP has been applied in transplantation studies aimed at identifying novel proteoform diagnostic and prognostic biomarkers of graft rejection and dysfunction.…”

“…In TDP, which is often coupled with LC, proteoforms are separated and directly ionized into mass spectrometers where the intact mass spectra (MS 1 ) are collected, and ions further fragmented (MS 2 ) for sequencing and PTM site identification ( Figure 2B ). Further advantages and limitations of TDP and BUP were reviewed elsewhere ( 20 , 82 ).…”

“…MS-based proteomics is a promising approach for SOT biomarker and therapeutic target discovery by providing global profiling and quantitative readout of proteoform changes ( 20 , 100 ). However, current proteomic workflows in SOT research focus on the analysis of bulk clinical samples.…”

“…Mass spectrometry (MS)-based proteomics can elucidate biological processes in depth ( 18 , 19 ) and has been extensively used to analyze the protein composition of a variety of clinical samples from transplant recipients ( 20 ). There are two general approaches for performing MS-based proteomics analysis: Bottom-up (BUP) and Top-down proteomics (TDP).…”