studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1065A
1756
Dual CCR2/CCR5 Antagonist Cenicriviroc Leads to
Potent and Significant Reduction in Proinflammatory
CCR2+ Monocyte Infiltration in Experimental Acute Liver
Injury
Oliver Krenkel 1 , Tobias Püngel 1 , Jana C. Mossanen 1 , Can Ergen 1 ,
Felix Heymann 1 , Eric Lefebvre 2 , Christian Trautwein 1 , Frank
Tacke 1 ; 1 Medical Clinic III, University Hospital Aachen, Aachen,
Germany; 2 Tobira Therapeutics Inc., San Francisco, CA
Aim of the study: Acute liver failure (ALF) is a life-threatening
condition with rapid deterioration of hepatic function and
limited therapeutic options. In mouse models, liver injury by
toxic agents like carbon tetrachloride (CCl4) or acetaminophen
(APAP) leads to rapid pro-inflammatory monocyte infiltration
into the liver via the CCR2–CCL2 (a.k.a. MCP-1) chemokine
pathway. Cenicriviroc (CVC) is an oral, once-daily CCR2/
CCR5 antagonist currently evaluated in a Phase-2b clinical trial
in adults with NASH and liver fibrosis. We therefore evaluated
CVC for inhibiting monocyte infiltration in CCl4 and APAP-induced
acute liver injury in vivo. Methods: C57BL/6J (WT) and
CCR2-deficient mice were subjected to ALF either by CCl4
(0.6 ml/kg IP) or APAP (250 mg/kg IV). In both models, mice
received either CVC (100 mg/kg) or vehicle by oral gavage.
Liver injury and immune cell phenotypes were analyzed. For
mechanistic studies, monocyte-derived macrophage subsets
and resident macrophages (Kupffer cells) were sorted by FACS
from injured livers and subjected to array-based Nanostring
gene expression analysis. Results: Both CCl4 and APAP led
to a rapid and massive accumulation of Ly6C+, monocyte-derived
macrophages in injured livers, dependent on the chemokine
receptor CCR2. Oral administration of CVC significantly
reduced pro-inflammatory Ly6C+ monocytes in blood (p