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

doi:10.1172/jci.insight.89679

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

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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.

Original language	English (US)
Article number	e89679
Journal	JCI insight
Volume	1
Issue number	20
DOIs	https://doi.org/10.1172/jci.insight.89679
State	Published - Dec 8 2016

ASJC Scopus subject areas

Medicine(all)

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Sosa, R. A., Zarrinpar, A., Rossetti, M., Lassman, C. R., Naini, B. V., Datta, N., Rao, P., Harre, N., Zheng, Y., Spreafico, R., Hoffmann, A., Busuttil, R. W., Gjertson, D. W., Zhai, Y., Kupiec-Weglinski, J. W., & Reed, E. F. (2016). Early cytokine signatures of ischemia/ reperfusion injury in human orthotopic liver transplantation. JCI insight, 1(20), Article e89679. https://doi.org/10.1172/jci.insight.89679

Sosa, RA, Zarrinpar, A, Rossetti, M, Lassman, CR, Naini, BV, Datta, N, Rao, P, Harre, N, Zheng, Y, Spreafico, R, Hoffmann, A, Busuttil, RW, Gjertson, DW, Zhai, Y, Kupiec-Weglinski, JW & Reed, EF 2016, 'Early cytokine signatures of ischemia/ reperfusion injury in human orthotopic liver transplantation', JCI insight, vol. 1, no. 20, e89679. https://doi.org/10.1172/jci.insight.89679

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title = "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.",

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

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doi = "10.1172/jci.insight.89679",

language = "English (US)",

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T1 - Early cytokine signatures of ischemia/ reperfusion injury in human orthotopic liver transplantation

AU - Sosa, Rebecca A.

AU - Zarrinpar, Ali

AU - Rossetti, Maura

AU - Lassman, Charles R.

AU - Naini, Bita V.

AU - Datta, Nakul

AU - Rao, Ping

AU - Harre, Nicholas

AU - Zheng, Ying

AU - Spreafico, Roberto

AU - Hoffmann, Alexander

AU - Busuttil, Ronald W.

AU - Gjertson, David W.

AU - Zhai, Yuan

AU - Kupiec-Weglinski, Jerzy W.

AU - Reed, Elaine F.

PY - 2016/12/8

Y1 - 2016/12/8

N2 - 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.

AB - 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.

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

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