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Basic science
P33 Treatment with Toll-like receptor 4 antagonist restores the inflammatory cellular immune dysfunction in acetaminophen induced acute liver failure mice
  1. N Shah,
  2. M Montes de Oca,
  3. N Shah,
  4. D Dhar,
  5. M Jover-Cobos,
  6. N Alun Davies,
  7. R Mookerjee,
  8. R Jalan
  1. Institute of Hepatology, University College London, UK

Abstract

Introduction Acute liver failure (ALF) is a rare, catastrophic syndrome commonly caused by acetaminophen (APAP) that results in the death of about 40% patients. In addition to liver dysfunction, its outcome is critically dependent upon the severity of inflammation. Paradoxically, infection complicates the outcome of patients with ALF. Toll-like receptor 4 (TLR4) plays an important role in the innate immune response recognising and mediating pro-inflammatory cytokine release.

Aim The aims of this study were to characterise the cellular immune response in APAP induced ALF in mice and to determine whether treatment with a specific TLR4 antagonist (STM28) restores cellular immune dysfunction.

Method CD1 (n=18) mice were studied (Sham, n=6; APAP (500 mg/kg IP), n=6; and APAP (500 mg/kg IP) plus STM-28, 20 ug prior to and after 6 h, n=6). The mice were sacrificed after 8 h. Peripheral blood was stained with fluorochrome-labelled antibodies specific for peripheral blood myeloid cells, dendritic cells (plasmacytoid and myeloid, expression of CD86 in myeloid); monocytes (resident and inflammatory); total granulocytes and neutrophils; CD4/CD8 T-cells and the expression of CD25 in CD4T cell populations; B cells and NK cells. Flow cytometric analysis was performed on a FACS Canto II. Biochemistry was measured spectrophotometrically.

Results Compared with sham animals, ALF was associated with widespread and profound abnormalities in cellular immune responses which were significantly improved in the group treated with TLR4 antagonist after APAP administration; significant improvement was observed in (STM28 vs APAP): total myeloid cells (39% vs 57%, p=0.0002), neutrophils (21% vs 37%, p=0.005), total granulocytes (28% vs 48%, p=0.0016), monocytes (6% vs 11%, p=0.0009) and resident monocytes, which are able to differentiate into macrophage (7% vs 15%, p=0.01). No significant differences were observed in subtypes of myeloid and plasmocytoid dendritic cells (54% vs 56% and 15% vs 10%, respectively), T-lymphocytes (16% vs 14%), B cells (7% vs 6%) and NK cells (1% vs 1%). These decrease in cellular inflammatory response was associated with a significant reduction in markers of liver injury (ALT: p<0.001; Ammonia: p<0.01).

Conclusion The results of this study suggest profound cellular immune dysfunction in APAP induced ALF mice which have a predominant pro-inflammatory phenotype. This dysfunction can be significantly improved by treatment with a TLR4 antagonist. This restoration of immune dysfunction is associated with significantly less liver injury indicating that TLR4 antagonism may have important therapeutic potential in APAP induced ALF.

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