Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Ischemia-reperfusion injury (IRI) elicits cellular damage which triggers a pro-inflammatory immune response that can lower allograft survival in orthotopic liver transplant (OLT) patients. In our OLT patient cohort, 56/113 (50%) had biopsy-proven IRI (IRI+), but patients with alcoholism (EtOH+) as an etiology necessitating OLT were disproportionally affected (21/33; 64% IRI+). The innate immune response can either promote or help resolve IRI depending on its activation to a pro- or anti-inflammatory state. Therefore, we tested EtOH- and EtOH+ OLT patient blood for differences in cytokines and the effect of these cytokines on myeloid cell differentiation.
*Methods: OLT patient peripheral blood was collected pre-OLT (PO). Two intraoperative blood samples were also collected: portal vein blood before liver reperfusion (PV) and immediately following liver reperfusion (LF). 38-plex Luminex cytokine analysis was performed on all blood samples. IHC for neutrophil and myeloid cell infiltration was performed on intraoperative pre- and post-reperfusion biopsies of donor organs. Healthy third-party monocytes were exposed to LF blood for 3 days; a panel of immunomodulatory surface markers was analyzed by flow cytometry.
*Results: EtOH+ patient blood had higher levels of cytokines compared to EtOH- patient blood at all timepoints: PO (Flt3L, p<0.05), PV (IL3, IL1Ra, p<0.05; IL8, MIP1β, p<0.01); and LF (IL3, p<0.05). Paired analysis showed larger decreases between corresponding PV and LF samples in EtOH+ patients for CXCL1 (p<0.05) and IL8 (p<0.01) compared to EtOH- patients. Neutrophil infiltration trended towards a significant increase from pre- to post-reperfusion biopsies in EtOH+ patients (p=0.056). Myeloid infiltration also increased pre-to post-reperfusion in EtOH+ patients (p<0.05). No such trends were seen in EtOH- patient biopsies. EtOH+ patient LF increased Gal-9 expression (p<0.05) and EtOH- patient LF induced TIM-4 (p<0.05) and PD-L1 (p=0.061) expression on monocyte-derived macrophages.
*Conclusions: EtOH+ OLT recipients showed higher Flt3L, IL3, MIP1β, IL8, and CXCL1 levels that can increase dendritic cell development (Flt3L) and neutrophil chemotaxis (others). Exposure to EtOH+ LF polarized monocytes to a more pro-inflammatory phenotype with increased Gal-9 expression, and a concurrent decrease of TIM-4 and PD-L1. Together, the pro-inflammatory immune profile seen before, during, and after allograft reperfusion can be a contributing factor to the disproportionate occurrence of IRI in EtOH+ OLT patients.
To cite this abstract in AMA style:Terry AQ, Sosa RA, Rossetti M, Li F, Nevarez-Mejia J, Naini BV, Kaldas FM, Groysberg VM, Younan SM, Busuttil RW, Gjertson DW, Kupiec-Weglinski JW, Reed EF. The Pro-Inflammatory Profile of Alcoholic Patients Increases Risk for Ischemia-Reperfusion Injury During Orthotopic Liver Transplantation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/the-pro-inflammatory-profile-of-alcoholic-patients-increases-risk-for-ischemia-reperfusion-injury-during-orthotopic-liver-transplantation/. Accessed May 7, 2021.
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