studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 845A
1288
High baseline expression of type 1 interferon (IFN)-inducible
genes involved in cell-autonomous immunity
predicts mortality in patients with decompensated alcoholic
cirrhosis
Marc Pineton de Chambrun 1 , Emmanuel Weiss 1 , Pierre-Emmanuel
Rautou 2 , Magali Fasseu 1 , Mikhael Giabicani 1 , Rakhi Maiwall
3 , Dominique Valla 2,1 , Didier Lebrec 2,1 , Francois Durand 2,1 ,
Pierre de la Grange 4 , Sophie Lotersztajn 1,2 , Richard Moreau 1,2 ;
1 UMR S1149, Center for Research on Inflammation (CRI), Inserm
and Paris Diderot University, Clichy, France; 2 DHU Unity, Service
d’Hépatologie, Hôpital Beaujon, Clichy, France; 3 Hepatology
Department, Institute of Liver and Biliary Science, New Delhi,
India; 4 Genosplice, Paris, France
Background & Aims: Although systemic inflammation is
believed to be a major driver of mortality in patients with
decompensated alcoholic cirrhosis, its mechanisms are unclear.
We hypothesized that baseline expression levels of genes
involved in cell-autonomous immunity (most of which are type
1 IFN-inducible) and/or of genes encoding secreted inflammatory
cytokines or chemokines by circulating mononuclear cells
in patients with cirrhosis may be related to patient outcome.
Thus, we measured the baseline gene expression in peripheral
blood mononuclear cells (PBMCs) from patients with decompensated
alcoholic cirrhosis and investigated their relationship
with the risk of death. Methods: PBMCs were isolated in 98
non infected patients (MELD score: 19 (15-24)) and 50 healthy
subjects. Using RT-qPCR, we monitored 52 type 1 IFN-inducible
genes and 10 IFN-non-inducible genes encoding ‘traditional’
secreted inflammatory cytokines (e.g., IL6) or chemokines (e.g.,
CXCL1). We also used a prespecified IFN score (a composite
of type 1 IFN-inducible genes: OAS2, MX2, DDX58, GBP4,
IFIH1, TRIM22, IFIT1, CXCL10). Gene expression in ‘cirrhotic
cells’ was normalized using expression in ‘healthy’ cells.
Patients were then followed-up for 10±12 months, until death,
transplantation or the end of the study. Results: In univariate
analysis, a higher MELD score, higher baseline expression of
9 IFN-inducible genes as well as higher IFN score values were
significant predictors of death. In contrast, cytokine or chemokine
gene expressions were not significantly related to death. In
bivariate analysis including the IFN and MELD scores, only the
former significantly predicted death (RR=3.58; 95% CI, 1.18-
10.91; P=0.02). These results were mainly due to the elevated
intrinsic prognostic value of OAS2 (RR=2.49; P=0.04) and
MX2 (RR=1.35; P=0.01). It is interesting to note that IFI35 and
IFI44, two genes not included in the IFN score were significant
predictors of death independent of the MELD score. Additional
experiments performed in blood from patients with early septic
shock with (n=7) or without (n= 7) cirrhosis showed that the
IFN score was 2.3 higher in patients with than in those without
cirrhosis (due to higher values of OAS2, IFIT1, GBP4). Conclusions:
In PBMCs from patients with decompensated alcoholic
cirrhosis, higher baseline levels of type 1 IFN-inducible genes
involved in cell-autonomous immunity, but not expression of
genes encoding secreted inflammatory cytokines/chemokines,
are highly predictive of the risk of death. Deregulation of type 1
IFN-inducible gene expression in circulating immune cells may
play a role in the mechanisms resulting in death from cirrhosis.
Disclosures:
Pierre-Emmanuel Rautou - Speaking and Teaching: Gilead
Dominique Valla - Advisory Committees or Review Panels: Sequana medical;
Consulting: IRIS
Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis,
BMS; Speaking and Teaching: Gilead
Pierre de la Grange - Management Position: GenoSplice
The following authors have nothing to disclose: Marc Pineton de Chambrun,
Emmanuel Weiss, Magali Fasseu, Mikhael Giabicani, Rakhi Maiwall, Didier
Lebrec, Sophie Lotersztajn, Richard Moreau
1289
Proportion of Intrahepatic CD56 Bright Natural Killer Cells
Correlates with Well-preserved Liver Function
Erin H. Doyle 1 , Adeeb Rahman 2 , Arielle L. Klepper 1 , Sang Kim 3 ,
Brandy M. Haydel 4 , Sander S. Florman 5 , M. Isabel Fiel 6 , Thomas
D. Schiano 5 , Andrea D. Branch 1 ; 1 Department of Liver Diseases,
Icahn School of Medicine at Mount Sinai, New York, NY; 2 Human
Immune Monitoring Core, Icahn School of Medicine at Mount
Sinai, New York, NY; 3 Department of Anesthesiology, The Mount
Sinai Hospital, New York, NY; 4 Center for Translational Transplant
Research, Icahn School of Medicine at Mount Sinai, New York,
NY; 5 Recanati Miller Transplantation Institute, The Mount Sinai
Hospital, New York, NY; 6 Department of Pathology, The Mount
Sinai Hospital, New York, NY
Background/Aim: HCV-related liver damage is largely
immune-mediated, but immunosuppression increases liver damage.
We investigated this paradox, seeking innate immune
cells whose prevalence correlates with well-preserved liver
function. Methods: Immune cells were isolated from 5-25 g
of tissue from 20 HCV-infected liver transplant patients using
mechanical disruption and enzymatic digestion. Peripheral
blood (obtained prior to surgery) and liver mononuclear
leukocytes were isolated on ficoll gradients and analyzed
by FACS and microarray. 8 subsets of innate immune cells
were enumerated. Pearson’s correlation coefficient was used
to find subsets whose prevalence correlated with liver status.
Microarrays were performed on RNA from cells with or without
exposure to TLR ligands. Results: Intrahepatic CD56 Bright /
CD16 - NK cells were strongly correlated with well-preserved
liver function and inversely related to markers of liver dysfunction:
MELD score (R 2 =0.41, p=0.007), total bilirubin (R 2 =0.74,
p