Ho Julie, Hirt-Minkowski Patricia, Wilkins John A
aManitoba Centre for Proteomics and Systems Biology, University of Manitoba and Health Sciences Centre bSection of Biomedical Proteomics cSection of Nephrology, Department of Internal Medicine dDepartment of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada eTransplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
Curr Opin Nephrol Hypertens. 2017 May;26(3):229-234. doi: 10.1097/MNH.0000000000000319.
Despite modern immunosuppression, renal allograft rejection remains a major contributor to graft loss. Novel biomarkers may help improve posttransplant outcomes through the early detection and treatment of rejection. Our objective is to provide an overview of proteomics, review recent discovery-based rejection studies, and explore innovative approaches in biomarker development.
Urine MMP7 was identified as a biomarker of subclinical and clinical rejection using two-dimensional liquid chromatography tandem-mass spectrometry (LC-MS/MS) and improved the overall diagnostic discrimination of urine CXCL10 : Cr alone for renal allograft inflammation. A novel peptide signature to classify stable allografts from acute rejection, chronic allograft injury, and polyoma virus (BKV) nephropathy was identified using isobaric tag for relative and absolute quantitation (TRAQ) and label-free MS, with independent validation by selected reaction monitoring mass spectrometry (SRM-MS). Finally, an in-depth exploration of peripheral blood mononuclear cells identified differential proteoform expression in healthy transplants versus rejection.
There is still much in the human proteome that remains to be explored, and further integration of renal, urinary, and exosomal data may offer deeper insight into the pathophysiology of rejection. Functional proteomics may be more biologically relevant than protein/peptide quantity alone, such as assessment of proteoforms or activity-based protein profiling. Discovery-based studies have identified potential biomarker candidates, but external validation studies are required.
尽管有现代免疫抑制手段，但肾移植排斥反应仍是导致移植肾丢失的主要原因。新型生物标志物可能有助于通过早期检测和治疗排斥反应来改善移植后的结果。我们的目标是概述蛋白质组学，回顾近期基于发现的排斥反应研究，并探索生物标志物开发的创新方法。
使用二维液相色谱串联质谱法（LC-MS/MS）将尿MMP7鉴定为亚临床和临床排斥反应的生物标志物，并改善了单独使用尿CXCL10:Cr对肾移植炎症的总体诊断区分能力。使用相对和绝对定量等压标签（TRAQ）和无标记质谱法鉴定了一种用于区分稳定移植肾与急性排斥反应、慢性移植肾损伤和多瘤病毒（BKV）肾病的新型肽谱，并通过选择反应监测质谱法（SRM-MS）进行了独立验证。最后，对外周血单个核细胞的深入探索确定了健康移植肾与排斥反应中差异蛋白异构体的表达。
人类蛋白质组中仍有许多有待探索的内容，进一步整合肾脏、尿液和外泌体数据可能会更深入地了解排斥反应的病理生理学。功能蛋白质组学可能比单纯的蛋白质/肽数量在生物学上更具相关性，例如对蛋白异构体的评估或基于活性的蛋白质谱分析。基于发现的研究已经确定了潜在的生物标志物候选物，但需要进行外部验证研究。
