Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation
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
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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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 7

Histopathological features of liver IRI in human OLT.

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Histopathological features of liver IRI in human OLT. (A) Representative...
(A) Representative histology of IRI+ liver allograft biopsies after reperfusion illustrating the range of IRI seen on histology. IRI+ patients demonstrate marked inflammation (red arrowheads) and/or necrosis (black arrowheads) along with one or more of the following: sinusoidal congestion (purple arrowheads), hepatocellular ballooning degeneration (orange arrowheads), macrovesicular steatosis (blue arrowheads), and/or cholestasis (green arrowheads). Scale bars: 50 μm. (B) Percentage of total IRI– or IRI+ patients that scored positive for 0 to 4 of the histopathological features of congestion, ballooning, steatosis, and/or cholestasis. NS, none scored for that data point. (C) Percentage of total IRI– or IRI+ patients either negative or positive for indicated histopathological features. (D) AST values for IRI– or IRI+ OLT recipients that presented with either 0 histopathological features or at least 1 (≥1) additional histopathological feature(s) evaluated (congestion, ballooning, steatosis, and/or cholestasis). 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 time point. n = 53; 26 IRI– and 27 IRI+. *P < 0.05, **P < 0.01. Statistical significance was determined using 1-way ANOVA with post-hoc Bonferroni for multiple comparisons and Bartlett’s test for equal variances.