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 Medicine 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 1

Recipient clinical tests of liver function after OLT-IRI correlate with IRI.

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Recipient clinical tests of liver function after OLT-IRI correlate with ...
Four clinical liver function tests were performed on recipient circulating peripheral blood taken on days 1–7 after transplant (D1–D7). Data are presented as Tukey box-and-whisker plots: whiskers are inner fences reaching 1.5 times the interquartile range and boxes represent the interquartile ranges, dots indicate outlying values, and lines represent median values for each day: bilirubin (mg/ml), ALT and AST (U/l), or INR. n = 53; 26 IRI– and 27 IRI+. *P < 0.05. The Wilcoxon rank-sum test was used for comparison between IRI+ and IRI– patient groups.