Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation

Liu, Xiaowen; Yue, Zongliang; Yu, Jeffrey; Kushekhar, Kushi; Zhang, Qing; Ogata, Yuko; Gafken, Philip R.; Inamoto, Yoshihiro; Gracon, Adam; Wilkes, David S.; Lee, Stephanie J.; Chen, Jake Y.; Paczesny, Sophie

doi:10.1111/ajt.13750

Cited by 27 publications

(19 citation statements)

References 52 publications

(38 reference statements)

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“…New modalities, such as parametric response mapping from high-resolution inspiratory/expiratory CT scans, which quantify the degree of functional small airway disease relative to normal lung parenchyma, have shown promise in differentiating BOS from pulmonary infection without BOS and could offer a noninvasive means of diagnosing early pulmonary cGVHD in children without the need for PFTs. 41 Cellular and plasma biomarkers, such as higher percentages of CD19 + CD21 Low B cells and elevated B-cell activating factor, 42 matrix metalloproteinase-3, 43 and Krebs Von Den Lungen-6, 44 have also been found to be potential biomarkers for pulmonary BOS following allo-HSCT, which could further aid in the early asymptomatic diagnosis of the disorder and act synergistically with other noninvasive diagnostic tests. Further, although the NIH-CC require the absence of infection to diagnose BOS, given the frequency of concurrent respiratory infections in children, this may not be possible.…”

Section: Discussionmentioning

confidence: 99%

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

Cuvelier

Nemecek

Wahlstrom

et al. 2019

Blood

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Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

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Section: Discussionmentioning

confidence: 99%

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

Cuvelier

Nemecek

Wahlstrom

et al. 2019

Blood

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“…55 MMP-3 was also correlated with bronchiolitis obliterans diagnosis. 85 Recently, both CXCL9 and CXCL10 were significantly correlated with cGVHD diagnosis in the first replication cohort, but only CXCL10 was in the second. 86 In another study, gene expression profiling of circulating monocytes from cGVHD patients revealed significant upregulation of IFN-inducible (including CXCL9 and CXCL10) and damage-response genes in cGVHD patients compared with controls.…”

Section: Cytomicsmentioning

confidence: 97%

Biomarkers for posttransplantation outcomes

Paczesny

2018

Blood

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During the last decade, the development of biomarkers for the complications seen after allogeneic hematopoietic stem cell transplantation has expanded tremendously, with the most progress having been made for acute graft-versus-host disease (aGVHD), a common and often fatal complication. Although many factors are known to determine transplant outcome (including the age of the recipient, comorbidity, conditioning intensity, donor source, donor-recipient HLA compatibility, conditioning regimen, posttransplant GVHD prophylaxis), they are incomplete guides for predicting outcomes. Thanks to the advances in genomics, transcriptomics, proteomics, and cytomics technologies, blood biomarkers have been identified and validated for us in promising diagnostic tests, prognostic tests stratifying for future occurrence of aGVHD, and predictive tests for responsiveness to GVHD therapy and nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. However, such blood tests are not yet available for routine clinical care. This article provides an overview of the candidate biomarkers for clinical evaluation and outlines a path from biomarker discovery to first clinical correlation, to validation in independent cohorts, to a biomarker-based clinical trial, and finally to general clinical application. This article focuses on biomarkers discovered with a large-scale proteomics platform and validated with the same reproducible assay in at least 2 independent cohorts with sufficient sample size according to the 2014 National Institutes of Health consensus on biomarker criteria, as well as on biomarkers as tests for risk stratification of outcomes, but not on their pathophysiologic contributions, which have been reviewed recently.

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“…An area under the receiver-operating characteristic (ROC) curve for MMP3 indicated a value of 0.77 (78). …”

Section: Soluble Biomarkersmentioning

confidence: 99%

B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2017

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main curative therapy for hematological malignancy such as leukemias, lymphomas, or multiple myelomas and some other hematological disorders. In this therapy, cure of hematological diseases relies on graft-versus-malignancy effects by allogenic immune cells. However, severe posttransplant treatment-associated complications such as acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) limit this approach. Most research into GvHD has concentrated on the aGvHD, while the more complex and multifaceted chronic form has been largely poorly investigated. cGvHD is a multi-organ autoimmune disorder and is the major cause of non-relapse morbidity and mortality following allo-HSCT, occurring in about 50% of patients, or 13,000–15,000 patients per year worldwide. Therefore, there is a high medical need for an early prediction of these therapy-associated toxicities. Biomarkers have gained importance over the last decade in diagnosis, in prognosis, and in prediction of pending diseases or side effects. Biomarkers can be cells, factors isolated from target tissues, or soluble factors that can be detected in body fluids. In this review, we aim to summarize some of the recent developments of biomarkers in the field of allo-HSCT. We will focus on cell-based biomarkers (B-cell subsets) for cGvHD and soluble factors including microRNA (miRNA), which are excreted into serum/plasma and urine. We also discuss the potential role of cytosolic and extracellular 70 kDa heat shock proteins (HSP70) as potential biomarkers for aGvHD and their role in preclinical models. Proteomic biomarkers in the blood have been used as predictors of treatment responses in patients with aGvHD for many years. More recently, miRNAs have been found to serve as a biomarker to diagnose aGvHD in the plasma. Another development relates to urine-based biomarkers that are usually detected by capillary electrophoresis and mass spectrometry. These biomarkers have the potential to predict the development of severe aGvHD (grades III–IV), overall mortality, and the pending development of cGvHD in patients posttransplant.

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Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation

Cited by 27 publications

References 52 publications

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

Biomarkers for posttransplantation outcomes

B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

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