Dataset Information

Critical role of OX40 in drug-induced acute liver injury.

ABSTRACT:

Background and purpose

The innate and adaptive immune systems both play important roles in drug-induced liver injury (DILI). However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co-stimulatory interactions between these immune systems. OX40 is a co-stimulatory molecule, but whether it regulates the intrahepatic immune response in DILI remains unknown.

Experimental approach

Acute liver injury was induced by paracetamol (acetaminophen), carbon tetrachloride (CCl₄ ), and d-galactosamine/LPS (GalN/LPS) in wild-type (WT) and Ox40 knockout (KO) mice, and disease progress was compared.

Key results

Plasma OX40 levels were significantly increased and were augmented in intrahepatic CD4⁺ T cells after paracetamol, CCl₄ , or GalN/LPS administration. Liver injury in Ox40-deficient mice was attenuated compared with that in WT mice. Compared with WT mice, hepatic infiltration of Th1 and Th17 cells and macrophages in Ox40 KO mice was reduced. Furthermore, adoptive transfer of Ox40 KO-CD4⁺ T cells to Rag1^-/- mice resulted in alleviated liver injury compared with WT-CD4⁺ T-cell transfer, with reduced liver infiltration of macrophages and pro-inflammatory cytokine secretion. Moreover, OX40/Fc stimulation in vitro revealed that soluble OX40 enhanced the biological function of murine macrophages, including up-regulation of genes associated with inflammation and tissue infiltration. Finally, soluble OX40 levels were significantly elevated in DILI patients compared with healthy controls.

Conclusion and implications

OX40 is a key molecule that promotes both pro-inflammatory macrophage and CD4⁺ T-cell function, exacerbating paracetamol-induced liver injury. OX40 could serve as a diagnostic index and therapeutic target of DILI.

SUBMITTER: Zhang C

PROVIDER: S-EPMC7312313 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsChronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity.Methods298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition.ResultsOut of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis.ConclusionsOne year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery.Lay summaryDrug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.