Alcoholic hepatitis (AH) is a severe form of chronic alcohol consumption-induced liver disease, which develops in as many as 35% of heavy drinkers. Hepatic inflammation is the cardinal feature of AH, and this progressive necro-inflammatory reaction in the liver results in a high, short-term mortality. To develop effective treatments for the disease, it is important to understand the underlying mechanisms by which alcohol-initiated hepatic inflammation are promoted, sustained and severely progress in AH patients. This U01 is a component of the Southern California Alcoholic Hepatitis Consortium U01 project (Consortium Coordinator: Tim Morgan, M.D.). The overarching goal of this UO1 consortium is to better understand and treat inflammation in AH. The specific goal of this application is to elucidate the molecular and cellular mechanisms of inflammation in AH with a particular focus on immunological parameters in the plasma and peripheral blood mononuclear cells (PBMC) in the patients with severe AH enrolled in this clinical trial.
The aims are as follows: (1) systemically examine the innate and adaptive immune status of AH patients prior to corticosteroid treatment. Plasma levels of proinflammatory and anti-inflammatory cytokines/mediators in control groups and AH patients will be measured by multiplex assays;the phenotypes and functions of PBMC subsets (NK/NKT, monocytes, Th1, Th2, Th17 and Treg) will be characterized by multi-parameter flow cytometric analysis;the phenotypes of inflammatory cells in the liver samples will be examined by immunohistochemical staining;the correlation of the immunological parameters with disease severity will be assessed. (2) Determine the role of damage-associated molecular pattern (DAMP) molecules in AH patients. The plasma levels of DAMP molecules (HMGB1, Mitochondrial DNA, S100A8/S100A9 and cytokeratin-18) in control groups and AH patients will be examined. Longitudinal monitoring of these DAMP molecules during this clinical trial will be carried out to correlate with disease severity, response to therapy and clinical outcomes. (3) Determine the correlation of immunological parameters with therapeutic response and clinical outcome in AH patients. The effect of steroid treatment on the immunological parameters (day1 and day 8) and their correlation with steroid response will be determined. Lymphocyte proliferation assay on day1 will be performed to predict the response to steroids. The effects of prednisolone+mycophenolate and prednisolone+rilonacept (anti-IL-1) treatment on the longitudinal changes of immunological parameters will be examined during the clinical trial (day1, 8, 15, 29 and at 3months);the correlation of the immunological parameters with occurrence of infections will be assessed. The elucidation of these three aims will lead to an improved understanding of the role and interplay of the immune system in inflammation in AH and will identify potential biomarkers for disease severity, response to therapy and clinical outcomes of AH patients.

Public Health Relevance

Alcoholic hepatitis is a severe form of chronic alcohol consumption-induced liver disease, which is a major medical, financial and social issue in the United States. This application is aiming at developing a detailed understanding of the immunological pathways leading to hepatic inflammation in patients with severe alcoholic hepatitis and identifying biomarkers to predict disease severity and provide guidance to effective treatment of alcoholic liver disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-JJ (07))
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Orosz, Andras
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Suda, Jo; Dara, Lily; Yang, Luoluo et al. (2016) Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-?B. J Immunol 197:3120-3129
Dara, Lily; Liu, Zhang-Xu; Kaplowitz, Neil (2016) Questions and controversies: the role of necroptosis in liver disease. Cell Death Discov 2:16089
Dara, Lily; Liu, Zhang-Xu; Kaplowitz, Neil (2016) Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications. Liver Int 36:158-65
Dara, Lily; Liu, Zhang-Xu; Kaplowitz, Neil (2016) A murder mystery in the liver: who done it and how? J Clin Invest 126:4068-4071