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CEACAM1 – p38 Signaling Axis Alleviates Peri-Transplant Liver Injury: From Mouse-to-Human

H. Hirao1, K. Nakamura1, S. Kageyama1, T. Ito1, K. Kadono1, M. Kujawski2, K. J. Dery1, R. A. Sosa1, E. F. Reed1, F. M. Kaldas1, R. W. Busuttil1, J. W. Kupiec‐Weglinski1

1UCLA, Los Angeles, CA, 2City of Hope, Duarte, CA

Meeting: 2019 American Transplant Congress

Abstract number: 274

Keywords: Biopsy, Ischemia, Liver grafts, Preservation

Session Information

Date: Monday, June 3, 2019

Session Name: Concurrent Session: Ischemia Reperfusion & Organ Rehabilition II

Session Time: 2:30pm-4:00pm

 Presentation Time: 2:30pm-2:42pm

Location: Room 313

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*Purpose: Although CEACAM1 (CM1; carcinoembryonic antigen-related cell adhesion molecule 1; CD66a) regulates hepatic metabolism, its role in orthotopic liver transplantation (OLT) is unknown. A recent study identified P38 MAPK signaling in the mechanism of cell death. We analyzed mouse OLTs and human OLT biopsies (Bx) to determine as to whether/how hepatocyte CM1-p38 axis may contribute to OLT outcomes.

*Methods: WT or CM1-deficient (CM1-KO) mouse livers (C57/BL6) were transplanted, after cold storage (UW/4℃/18h), to syngeneic WT recipients, and sampled at 6h post-OLT. Separate groups of cold-stored WT or CM1-KO livers were perfused with saline to collect liver flush (LF). Bone marrow-derived macrophage (BMDM) cultures were then stimulated with LF from WT vs. CM1-KO cold-stored livers. In the clinical arm, human cold-stored pre-OLT Bx (n=63) were screened for CM1/phosphor-p38 (pP38) expression by Western blots (WB), while corresponding post-OLT Bx (at 2h post-reperfusion) were screened by RT-PCR.

*Results: Compared with WT>WT mouse OLTs, donor liver CM1 disruption (CM1-KO>WT) aggravated OLT damage, evidenced by: 1/ sALT/sAST levels (n=10/10, p<0.05),; 2/Suzuki's histological hepatic grading (p<0.05); 3/ frequency of TUNEL+ cells (p<0.05); 4/ increased serum HMGB1 levels (ELISA, p<0.05); 5/ enhanced Ly6G+/CD11b+ cell infiltration (IHC, p<0.05); and 5/ raised MCP1/CXCL2/CXCL10/IL1β/IL2 (p<0.05). In primary mouse hepatocyte cultures, CM1 deficiency augmented pP38 expression (WB, p<0.05), evidenced by AST/ALT release into culture medium (p<0.05). Moreover, CM1-deficient cold-stored livers showed enhanced pP38 expression (p<0.05), with LF from CM1-KO grafts enriched in HMGB1/Histone H3 (WB, p<0.05), and readily triggering BMDM activation in vitro, evidenced by MCP1/CXCL2/CXCL10 levels (p<0.05), as compared to LF from WT grafts. In the clinical arm, pre-OLT CM1 levels in human hepatic Bx negatively correlated with pP38 (r=-0.369, p=0.003); sALT (r=-0.315, p=0.012) and sAST(r=-0.269, p=0.033) at POD1. Unlike in pre-OLT "high" CM1 group (n=31), pre-OLT "low" CM1 livers (n=32) were characterized by: 1/ increased sAST (710±299 vs 268±40 IU/L, p=0.014) and sALT (420±49 vs 287±45 IU/L, p=0.021) at POD1; 2/ enhanced TLR4/CD86/CD68 (macrophage markers), Cathepsin G (neutrophil marker), CD4/CD28 (T cell markers) in OLT Bx; and 3/ impaired overall graft survival (3-y: 76.7 vs 90.8%, p=0.1219) and rejection-free graft survival (3-y: 64.7 vs 81.5%, p=0.1383).

*Conclusions: This translational study identifies a novel hepatocyte CM1-P38 signaling pathway, which protects liver grafts against ischemia/surgery stress and controls innate – adaptive immune interface/OLT outcomes. Hence, CM1-P38 axis represents not only a new biomarker of hepatocellular function in cold-stored livers, but may also serve as a target for therapeutic intervention in OLT recipients.

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To cite this abstract in AMA style:

Hirao H, Nakamura K, Kageyama S, Ito T, Kadono K, Kujawski M, Dery KJ, Sosa RA, Reed EF, Kaldas FM, Busuttil RW, Kupiec‐Weglinski JW. CEACAM1 – p38 Signaling Axis Alleviates Peri-Transplant Liver Injury: From Mouse-to-Human [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/ceacam1-p38-signaling-axis-alleviates-peri-transplant-liver-injury-from-mouse-to-human/. Accessed February 27, 2021.

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