Proteomic peptide profiling for preemptive diagnosis of acute graft-versus-host disease after allogeneic stem cell transplantation

Weissinger, Eva M.; Metzger, Jochen; Dobbelstein, Christiane; Wolff, Daniel; Schleuning, Michael; Kuzmina, Zoya; Greinix, Hildegard; Dickinson, Anne M.; Mullen, William; Kreipe, Hans; Hamwi, Iyas; Morgan, Michael; Krons, Annika; Tchebotarenko, I; Ihlenburg-Schwarz, D; Dammann, Elke; Collin, Matthew; Ehrlich, Steve; Diedrich, Helmut; Stadler, Michael; Eder, Matthias; Holler, Ernst; Mischak, Harald; Krauter, Jürgen; Ganser, Arnold

doi:10.1038/leu.2013.210

Cited by 47 publications

(33 citation statements)

References 34 publications

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“…Mass spectrometry-based analysis of the endogenous urinary peptidome (i.e., 5 not generated by trypsin digestion) allows the assessment of thousands of urinary peptides at once. Combined in multi-molecular classifiers of tens to hundreds of peptides, these urinary peptides have proven their ability to faithfully describe complex diseases including kidney disease 17,20 , cardiovascular disease 21 , graft-versus-host disease 22 , and cholangiocarcinoma 23 .…”

Section: Introductionmentioning

confidence: 99%

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

Klein

Ramírez-Torres

Ericsson

et al. 2016

Kidney International

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Diabetic nephropathy (DN) is among the most frequent complications of diabetes and the first cause of end-stage renal disease. Despite being successful in animal models, the majority of clinical trials for novel drugs targeting DN failed. This lack of translational value may in part be due to an inadequate comparability of human disease and animal models that often capture only a few aspects of disease. Here we overcome this limitation by developing a multimolecular non-invasive humanized readout of DN based on urinary peptidomics. The diseasemodified urinary peptides of two type 2 diabetic (T2D) DN mouse models were identified and compared with previously validated urinary peptide markers of DN in humans to generate a classifier composed of 21 ortholog peptides. This classifier predicted the response to disease and treatment with inhibitors of the renin-angiotensin system (RASi) in mice. The humanized classifier was significantly correlated with glomerular lesions. Using a human T2D validation cohort consisting of 207 patients, the classifier also distinguished between patients with and without DN, and response to RASi. Our approach demonstrates that a combination of multiple molecular features similar in both human and animal disease could provide a step change in translational drug discovery research in T2D-DN nephropathy.

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Section: Introductionmentioning

confidence: 99%

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

Klein

Ramírez-Torres

Ericsson

et al. 2016

Kidney International

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“…An acute GVHD-specific urinary proteome classifier was recently validated in 423 alloHCT recipients; the classifier correctly identified patients developing severe acute GVHD 14 days before any clinical signs and did so with acceptable predictive value (82.4% sensitivity and 77.3% specificity). 190 The classifier, consisting of 17 peptides derived from albumin, β 2 -microglubulin, CD99, fibronectin, and various collagen α-chains, indicated inflammation, T-cell activation, and changes in the extracellular matrix as early signs of GVHD-induced organ damage. 190 Recently, a panel of six protein biomarkers – IL-2 receptor-α; tumor necrosis factor receptor-1; hepatocyte growth factor; IL-8; elafin, a skin-specific marker; and REG3a, a gastrointestinal tract–specific marker – relevant to GVHD treatment has been identified using proteomics discovery and validation strategies.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

Bemer

Long‐Boyle

2015

Clin Pharmacokinet

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Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article, part II, we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. There are several studies demonstrating that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared to MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include “–omics” based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics and proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.

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“…Since the CE-MS technology has proven to meet all analytical requirements for diagnostic systems, as already demonstrated in a recent technical report and large-scale prospective and/or longitudinal clinical studies, [18][19][20][21][22] no transfer of the CC BPA/UPA test to another analytical platform is required for the use of the proteomic test in a routine clinical setting.…”

Section: Discussionmentioning

confidence: 99%

A combined bile and urine proteomic test for cholangiocarcinoma diagnosis in patients with biliary strictures of unknown origin

Voigtländer¹,

Metzger²,

Jäger³

et al. 2017

Journal of Hepatology

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Proteomic peptide profiling for preemptive diagnosis of acute graft-versus-host disease after allogeneic stem cell transplantation

Cited by 47 publications

References 34 publications

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

A combined bile and urine proteomic test for cholangiocarcinoma diagnosis in patients with biliary strictures of unknown origin

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