Session Name: Biomarker Discovery and Immune Modulation
Session Date & Time: None. Available on demand.
*Purpose: Although CEACAM1 (CC1; carcinoembryonic antigen-related cell adhesion molecule 1; CD66a) regulates innate-adaptive immunity, its role in orthotopic liver transplantation (OLT) remains unknown. CC1 expresses two isoforms, i. e., CC1 short (CC1S) and CC1 long (CC1L) isoform. The CC1L isoform in mouse OLTs has been confined primarily to host-derived circulating infiltrating neutrophils. Here, we analyzed mouse and human OLT biopsies (Bx) to determine as to whether/how neutrophil CC1L isoform may contribute to OLT outcomes.
*Methods: In the experimental arm, donor WT (C57/BL6) livers were transplanted, after cold storage (4oC/18h), to groups of syngeneic WT or CC1-deficient
(CC1-KO) mouse recipients, and sampled at 6h post-OLT. In parallel in vitro study, neutrophils isolated from WT or CC1-KO mice were cultures with: 1/ LPS or IL-4 adjunct; or 2/ co-cultured with WT bone marrow macrophages stimulated with LPS. In the clinical arm, human hepatic biopsies obtained at 2h post-OLT Bx
(n=55) were screened for CC1L, ATG5, ATG7, LC3B expression (Western blots) and for pro-inflammatory phenotype (RT-PCR).
*Results: Mouse OLTs (WT) were negative for CC1L expression when transplanted to CC1-KO but not to WT recipients. Recipient CC1 null mutation augmented IRI-OLT (WT>CC1-KO) as evidenced by increased sAST/sALT levels (p<0.05), deteriorated pro-inflammatory cytokine/chemokine programs (p<0.05) and impaired post-LT autophagy induction. CC1-KO neutrophils showed higher amount of IL-1β/elastase expression and depressed arginase-1 after LPS challenge; and decreased p-stat6 levels in response to IL-4 stimulation. In neutrophil-macrophage co-culture system, CC1-proficient, but not CC1-KO neutrophils suppressed macrophage activation after LPS stimulation. Consistent with mouse data, CC1L expression in human liver Bx correlated positively with ATG7 (r=0.2628,
p=0.0526), ATG5 (r=0.2994, p=0.0264) and LC3B (r=0.2739, p=0.0430). When divided into low (n=28) vs. high (n=27) CC1L expression groups, CC1L low human OLTs showed enhanced innate/adaptive immune activation, and higher incidence of early allograft dysfunction (EAD; 28.6% vs 11.1%).
*Conclusions: As a checkpoint regulator of IR-stress and sterile inflammation, neutrophil CC1L may serve as a novel biomarker and target for therapeutic modulation in OLT recipients.
To cite this abstract in AMA style:Hirao H, Kojima H, Kadono K, Dery KJ, Nakamura K, Farmer DG, Kaldas FM, Kupiec-Weglinski JW. Neutrophil CEACAM1 Induces Hepatic Autophagy and Shapes Innate-adaptive Immune Response in Liver Transplantation: From Mouse-to-human [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/neutrophil-ceacam1-induces-hepatic-autophagy-and-shapes-innate-adaptive-immune-response-in-liver-transplantation-from-mouse-to-human/. Accessed July 30, 2021.
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