Blockade of PD1 and TIM3 Restores Innate and Adaptive Immunity in Patients with Acute Alcoholic Hepatitis

Lee J L Markwick, Antonio Riva, Jennifer M Ryan, Helen Cooksley, Elena Palma, Tom H Tranah, Godhev K Manakkat Vijay, Nikhil Vergis, Mark Thursz, Alex Evans, Gavin Wright, Sarah Tarff, John O'Grady, Roger Williams, Debbie L Shawcross, Shilpa Chokshi

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152 Citations (Scopus)

Abstract

BACKGROUND & AIMS: Susceptibility to bacterial infection is a feature of alcohol-related liver disease (ALD). Programmed cell death 1 (PDCD1, also known as PD1), the T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3, also known as hepatitis A virus cellular receptor 2, HAVCR2) and their respective ligands-CD274 (also known as PDL1) and galectin-9-are inhibitory receptors that regulate the balance between protective immunity and host immune-mediated damage. However, their sustained hyper-expression promotes immune exhaustion and paralysis. We investigated the role of these immune inhibitory receptors in driving immune impairments in patients with ALD.

METHODS: In a prospective study, we collected blood samples from 20 patients with acute alcoholic hepatitis (AAH), 16 patients with stable advanced alcohol-related cirrhosis (ARC), and 12 healthy individuals (controls). Whole blood or peripheral blood mononuclear cells were assessed for expression of PD1, PDL1, TIM3, galectin-9, and toll-like receptors (TLRs) on subsets of innate and adaptive immune effector cells. We measured antibacterial immune responses to lipopolysaccharide (endotoxin) using ELISpot assays, and used flow cytometry to quantify cytokine production, phagocytosis and oxidative burst in the presence or absence of blocking antibodies against PD1 or TIM3.

RESULTS: Antibacterial innate and adaptive immune responses were greatly reduced in patients with AAH, compared with controls, whereas patients with ARC had less-severe dysfunctions in innate immune effector cells and preserved functional T-cell responses. Fewer T cells from patients with AAH produced interferon-γ (IFNγ) in response to LPS, compared with controls. Furthermore, patients with AAH had greater numbers of IL10-producing T cells, and reduced levels of neutrophil phagocytosis and oxidative burst in response to Escherichia coli stimulation, compared to controls. T cells from patients with AAH, but not ARC, expressed higher levels of PD1 and PDL1, or TIM3 and galectin-9, than T cells from controls. Antibodies against PD1 and TIM3 restored T-cell production of IFNγ, reduced the numbers of IL10-producing T cells, and increased neutrophil antimicrobial activities. Circulating levels of endotoxin in plasma from patients with AAH caused over expression of immune inhibitory receptors on T cells via TLR4 binding to CD14+ monocytes.

CONCLUSIONS: Antibacterial immune responses are impaired in patients with AAH. Lymphocytes from these patients express high levels of immune inhibitory receptors, produce lower levels of IFNγ, and have increased IL10 production due to chronic endotoxin exposure. These effects can be reversed by blocking PD1 and TIM3, which increase the antimicrobial activities of T cells and neutrophils.

Original languageEnglish
Pages (from-to)590-602.E10
JournalGastroenterology
Volume148
Issue number3
Early online date2 Dec 2014
DOIs
Publication statusPublished - 1 Mar 2015

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