Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation
Rebecca A. Sosa, … , Jerzy W. Kupiec-Weglinski, Elaine F. Reed
Rebecca A. Sosa, … , Jerzy W. Kupiec-Weglinski, Elaine F. Reed
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e89679. https://doi.org/10.1172/jci.insight.89679.
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Clinical Research and Public Health Immunology Transplantation

Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation

Abstract

BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant.

METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI–), clinical liver function tests early (days 1–7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion.

RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq.

CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment.

FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.

Authors

Rebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, Elaine F. Reed

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Figure 4

Recipient portal cytokines, chemokines, and growth factors cluster by donor contribution and then by IRI status.

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Recipient portal cytokines, chemokines, and growth factors cluster by do...
Thirty-eight cytokines, chemokines, and growth factors were measured by Luminex multiplex assay in portal blood of OLT recipients before (PV) or after (LF) it was flushed through the donor liver during reperfusion. Shown is a heatmap in which the rows represent cytokines, the columns represent IRI status at each time point, and the colors represent normalized median cytokine concentration values (white = low, red = high). The rows and columns are ordered based on the results of unsupervised hierarchical clustering, with dendrograms for the cytokines and patient groups shown on the vertical and horizontal axes, respectively.