Background T cell exhaustion has recently been proposed as an alternative mechanism to prevent memory development and tissue damage arising during ischemia-reperfusion injury (IRI) in murine orthotopic liver transplantation (OLT), with carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) identified as a key ligand for TIM-3-mediated negative immune regulation in the liver. In our cohort of human OLT patients, IRI⁺ recipients had a 12-fold higher ratio of TIM-1⁺:TIM-3⁺ CD4⁺ T cells at 3 months post-transplant than IRI^–. Aim We sought to investigate donor and recipient contributions to CEACAM1 expression in human OLT-IRI. Methods We compared the cellular expression of CEACAM1 biopsies obtained from the donor organ pre- and post-reperfusion with the recipient's portal blood. Additionally, we evaluated CEACAM1 expression of 3^rd party healthy donor monocytes co-cultured for 4 days with recipient portal blood obtained both pre- and post-reperfusion through the donor organ. Results Pre-reperfusion biopsies from IRI^– recipients (n=5) showed normal hepatic lateral surface CEACAM1 protein expression on bile canaliculi that was dramatically increased post-reperfusion, in stark contrast to IRI⁺ recipients (n=6) whose post-reperfusion hepatocytes were not CEACAM1⁺. Detached liver sinusoidal endothelial cells expressed high levels of CEACAM1 in IRI^– but not IRI⁺ biopsies. Although IRI⁺ biopsies contained larger myeloid infiltrates post- vs pre-transplant, only those found in IRI^– biopsies expressed CEACAM1. Blood from either group (n=47; 24 IRI⁺, 23 IRI^–) obtained before reperfusion increased the frequency of CEACAM1⁺ monocytes; however, IRI⁺ blood obtained after reperfusion decreased the frequency of CEACAM1⁺ monocytes compared to IRI^– post-reperfusion blood. Conclusion These results suggest that 1) loss of hepatic CEACAM1 in the pre-transplant donor allograft contributes to IRI in OLT, 2) one or more soluble factors in IRI+ recipient blood can decrease CEACAM1 expression, and 3) increased expression of CEACAM1 in human OLT is cytoprotective during IRI, potentially leading to T cell exhaustion, thereby improving IRI-related outcome in recipients.

CITATION INFORMATION: Sosa R., Nevarez-Mejia J., Rossetti M., Zarrinpar A., Kaldas F., Lassman C., Naini B., Datta N., Busuttil R., Gjertson D., Kupiec-Weglinski J., Reed E. Increased Expression of CEACAM1 is Cytoprotective during Ischemia-Reperfusion Injury in Human Orthotopic Liver Transplantation Am J Transplant. 2017;17 (suppl 3).

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