Elevated ST2 Distinguishes Incidences of Pediatric Heart and Small Bowel Transplant Rejection

Abstract

Elevated serum soluble (s) Suppressor of Tumorigenicity 2 (ST2) 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 non-rejection (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 rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted TNF-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 non-invasive diagnosis of rejection.

Role of Soluble ST2 as a Marker for Rejection after Heart Transplant

“…The role of sST2 as a biomarker to predict acute rejection after HTx has been investigated previously 16)17). Pascual-Figal et al16) reported that sST2 levels were increased as compared with the pre-rejection period, and decreased again after treatment of acute rejection.…”

“…However, correcting for confounding factors of the time after HTx, a statistical difference was not found. More recently, Mathews et al reported that a higher level of sST2 (>600 pg/mL) could discriminate graft rejection with an area under the curve of 0.72±0.05 in pediatric HTx patients 17). However, they had higher rates of rejection events, and included a large proportion of acute humoral rejection among the significant rejection group.…”

Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses

“…ST2 and sST2 are induced or augmented in leukocytes and stromal cells by pro-inflammatory cytokines, TLR ligands, and mechanical stress. Building upon our early rodent studies that established that ST2 is increased locally, but not systemically during rejection of heterotopic heart transplants (26), we showed that the alloimmune-associated pro-inflammatory cytokines increase graft ST2 during rejection episodes in pediatric SOTx recipients (73). Graft ST2 increases were reflected in increased serum sST2 levels that signified rejection in cohorts of small bowel or heart transplant recipients (73).…”

“…Building upon our early rodent studies that established that ST2 is increased locally, but not systemically during rejection of heterotopic heart transplants (26), we showed that the alloimmune-associated pro-inflammatory cytokines increase graft ST2 during rejection episodes in pediatric SOTx recipients (73). Graft ST2 increases were reflected in increased serum sST2 levels that signified rejection in cohorts of small bowel or heart transplant recipients (73). Similarly, high serum sST2 acts as a reliable biomarker predicting resistance in GVHD patients to corticosteroid therapy and non-relapse mortality (74).…”

New Insights into Graft-Versus-Host Disease and Graft Rejection

“…IL-33 can induce direct effects in ST2 + Tregs but also indirect effects via IL-33-responsive DCs (110). Interestingly, elevated levels of sST2 in plasma are observed during episodes of acute cardiac and small bowel allograft rejection in patients, suggesting that IL-33/ST2 signaling might be dysregulated in human transplantation (111,112).…”