Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis

Støy, Sidsel; Dige, Anders; Sandahl, Thomas Damgaard; Laursen, Tea Lund; Buus, Christian; Hokland, Marianne; Vilstrup, Hendrik

doi:10.1152/ajpgi.00200.2014

Cited by 34 publications

(25 citation statements)

References 49 publications

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“…LPMCs surface expression of the T cell activation markers was measured essentially as described [ 28 ]. Briefly, within one hour of the isolation, cells were incubated with heat-inactivated mouse serum (Invitrogen, cat.…”

Section: Methodsmentioning

confidence: 99%

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Administration of Panobinostat Is Associated with Increased IL‐17A mRNA in the Intestinal Epithelium of HIV‐1 Patients

Christensen

Dige

Vad-Nielsen

et al. 2015

Mediators of Inflammation

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Intestinal CD4+ T cell depletion is rapid and profound during early HIV-1 infection. This leads to a compromised mucosal barrier that prompts chronic systemic inflammation. The preferential loss of intestinal T helper 17 (Th17) cells in HIV-1 disease is a driver of the damage within the mucosal barrier and of disease progression. Thus, understanding the effects of new therapeutic strategies in the intestines has high priority. Histone deacetylase (HDAC) inhibitors (e.g., panobinostat) are actively under investigation as potential latency reversing agents in HIV eradication studies. These drugs have broad effects that go beyond reactivating virus, including modulation of immune pathways. We examined colonic biopsies from ART suppressed HIV-1 infected individuals (clinicaltrials.gov: NCT01680094) for the effects of panobinostat on intestinal T cell activation and on inflammatory cytokine production. We compared biopsy samples that were collected before and during oral panobinostat treatment and observed that panobinostat had a clear biological impact in this anatomical compartment. Specifically, we observed a decrease in CD69+ intestinal lamina propria T cell frequency and increased IL-17A mRNA expression in the intestinal epithelium. These results suggest that panobinostat therapy may influence the restoration of mucosal barrier function in these patients.

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Section: Methodsmentioning

confidence: 99%

“…Intracellular cytokine detection in LPMCs was performed essentially as described [ 28 ]. Briefly, freshly isolated cells were incubated unstimulated overnight at 37°C in flat-bottomed wells (Nunc, Denmark, cat.…”

Section: Methodsmentioning

confidence: 99%

Administration of Panobinostat Is Associated with Increased IL‐17A mRNA in the Intestinal Epithelium of HIV‐1 Patients

Christensen

Dige

Vad-Nielsen

et al. 2015

Mediators of Inflammation

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“…These populations include resident macrophages or KC, circulating macrophages, neutrophils, natural killer (NK) and natural killer T (NKT) cells [6,54,55,56,57]. Many inflammatory cytokines, such as TNFα, IL-1β, monocyte chemoattractant protein-1 (MCP-1) and IL-6 are also produced in and outside the liver.…”

Section: Key Players In Aldmentioning

confidence: 99%

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

2017

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Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.

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“…In cirrhosis, T cell depletion plays a key role in the pathogenesis of cirrhosis-associated immune dysfunction [1,2]. In addition, bacterial translocation (BT)-related expansion of splenic lymphoid tissue and inflammation, as well as splenic sequestration results in T lymphopenia [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice

Tsai,

Hsu,

Huang

et al. 2020

Cells

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Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. β-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of β1 and β2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of β1 and β2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.

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Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis

Cited by 34 publications

References 49 publications

Administration of Panobinostat Is Associated with Increased IL‐17A mRNA in the Intestinal Epithelium of HIV‐1 Patients

Administration of Panobinostat Is Associated with Increased IL‐17A mRNA in the Intestinal Epithelium of HIV‐1 Patients

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice

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