title: Elevated ST2 Distinguishes Incidences of Pediatric Heart and Small Bowel Transplant Rejection.
abstract: Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1β as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA.
authors.forename: L R
authors.initials: LR
authors.lastname: Mathews
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: J M
authors.initials: JM
authors.lastname: Lott
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: K
authors.initials: K
authors.lastname: Isse
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A
authors.initials: A
authors.lastname: Lesniak
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Division of General Internal Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: D
authors.initials: D
authors.lastname: Landsittel
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Demetris
authors.affiliation: Department of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: D F
authors.initials: DF
authors.lastname: Mercer
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: S A
authors.initials: SA
authors.lastname: Webber
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A
authors.initials: A
authors.lastname: Zeevi
authors.affiliation: Department of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: R T
authors.initials: RT
authors.lastname: Fischer
authors.affiliation: Division of Pediatric Cardiology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center and Division of Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: B
authors.initials: B
authors.lastname: Feingold
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: H R
authors.initials: HR
authors.lastname: Turnquist
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000032:analysis*; D002648:Child; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology; D006085:Graft Survival; D006331:Heart Diseases / Q000601:surgery; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D015994:Incidence; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000378:metabolism*; D007410:Intestinal Diseases / Q000601:surgery; D007421:Intestine, Small / Q000473:pathology / Q000637:transplantation*; D008297:Male; D010414:Pennsylvania / Q000453:epidemiology; D011183:Postoperative Complications; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D012333:RNA, Messenger
keywords: biomarker; biopsy; cytokines/cytokine receptors; diagnostic techniques and imaging; rejection