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848A AASLD ABSTRACTS HEPATOLOGY, October, 2015 1294 Chronic alcohol consumption skews hepatic dendritic cell homeostasis and reveals a novel potential cellular source of TNFα Holger Fey, Costica Aloman; Division of Gastroenterology/Liver Diseases (MC716), University of Illinois at Chicago, Chicago, IL Background/Aim: Alcohol abuse is one of the leading causes of chronic liver disease and liver-related mortality. Tumor necrosis factor alpha (TNFα) is considered a central mediator in the pathogenesis of alcoholic liver damage. Dendritic cells (DC) are mononuclear phagocytes and critical regulators of innate and adaptive immunity. Several populations of DC coexist in mouse and humans: classic DC (cDC) and plasmacytoid DC (pDC). In this study we investigated the effects of chronic alcohol exposure on hepatic DC homeostasis and their contribution to the hepatic cytokine environment. Methods: Alcohol (EtOH) was delivered in the drinking water to C57BL/6 mice at 20% v/v (Meadows-Cook diet). Hepatic DC sets and bone marrow (BM) progenitors of the myeloid lineage were analyzed by flow cytometry. Circulating growth factors involved in DC development (Flt3L, GM-CSF, M-CSF) were measured by ELISA. TNFα production was assessed by intracellular cytokine staining of hepatic leukocytes isolated after in vivo toll-like receptor (TLR) stimulation with TLR4 and TLR9 agonists. Results: C57BL/6 mice receiving alcohol in drinking water for 12 weeks have a 70% increase (P
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 849A recruitment under conditions of shear stress identified inflammatory cells that migrated into HSEC and subsequently exhibited novel cell-to-cell crawling. This process was dependent on IFN-γ and occurred predominantly in HSEC when compared to vascular endothelium. Expression of chemokine transcripts and transcellular permeability were similar in both endothelia, whereas distinct differences were identified in junctional molecule expression, with HSEC lacking occludin and expressing lower levels of JAM-A than vascular endothelium. In support of these findings immunofluorescent analysis of human liver tissue demonstrated CD3+/CD4+ cells within sinusoidal endothelial cells. Conclusion - We demonstrate a novel behaviour of lymphocyte migration which occurs during interactions with primary human HSEC. This process appears to be mediated by the unique junctional expression pattern of HSEC and microenvironmental stimuli such as IFN-γ. We believe this is a novel step in the adhesion cascade that could have implications for treating chronic inflammatory liver disease and modulating intrahepatic immunity. Disclosures: David H. Adams - Advisory Committees or Review Panels: GSK, Proximagen; Grant/Research Support: Takeda, Biotie Therapies, Novimmune, ChemoCentryx, Novimmune, Biotie Therapies; Patent Held/Filed: biotie therapies, Biotie Therapies, Biotie Therapies, Biotie Therapies, Biotie Therapies, Biotie Therapies, Biotie Therapies, Biotie Therapies The following authors have nothing to disclose: Shishir Shetty, Daniel A. Patten, Chris J. Weston 1297 Inhibition of the FGL2:FcγRIIB Immunosuppressive Pathway Restores Antiviral T and B Cell Responses During Chronic Viral Infection Ramzi Khattar, Olga Luft, Kaveh Farrokhi, Vanessa Rojas Luengas, Hassan Sadozai, Gary Levy, Nazia Selzner; University Health Network, Toronto, ON, Canada Background and Aims: HBV and HCV utilize host immunosuppressive pathways to limit antiviral T cell responses and promote the generation of dysfunctional T cells in a process termed T cell exhaustion. Recent reports have implicated the upregulation of immunosuppressive cytokines and involvement of Tregs as causative agents of persistent HBV and HCV infection. FGL2 is a potent immunosuppressive effector molecule of CD4 + C- D25 + TIGIT + FOXP3 + Treg. The role for FGL2 in establishing T cell exhaustion in chronic viral infection caused by LCMV Cl-13 was assessed. Methods: Fgl2 +/+ and fgl2 -/- mice were infected with 2x10 6 PFU of LCMV Cl-13. FGL2 was measured in plasma by ELISA. Frequencies of LCMV specific T cells were determined following stimulation with viral peptide. Neutralizing antibody titers were evaluated by plaque reduction assay. Viral titers in plasma and liver were assessed by an LCMV focus forming assay. Fgl2 +/+ were treated with neutralizing antibodies toward FGL2 and FCγRIIB and subsequently infected with 2x10 6 PFU of LCMV Cl-13. LCMV antiviral immune responses were measured. Results: Following infection with 2x10 6 PFU of LCMV Cl-13, plasma levels of FGL2 in Fgl2 +/+ mice increased (51.6±2.4 ng/mL) reaching maximum levels on day 7 pi (135.6±7.0 ng/mL; P
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1000A AASLD ABSTRACTS HEPATOLOGY, O
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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