Relative contribution of lymphocytes to hepatic ischemia reperfusion injury
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Date
02/07/2016Item status
Restricted AccessEmbargo end date
31/12/2100Author
Richards, James Alexander
Metadata
Abstract
Background
Hepatic ischemia reperfusion injury (IRI) results from the interruption and then
reinstatement of the liver’s blood supply. IRI involves both an ischemic and an
immune-mediated reperfusion phase of tissue injury; similar inflammatory events are
seen in other forms of acute (sterile) liver injury (ALI), including paracetamol toxicity.
Hypothesis
Irrespective of the primary insult, common pathways exist in the pathophysiology of
the lymphocyte-mediated secondary liver injury. Natural mechanisms exist to limit
lymphocyte function and these pathways can be targeted therapeutically by
immunomodulatory agents.
Aims
1. To assess the relative importance of different lymphocyte subsets in IRI.
2. To correlate observations in IRI with other models of ALI.
3. To identify possible pharmacological targets.
Materials and Methods
Three experimental murine models of acute liver injury were utilised to test this
hypothesis: murine model of warm hepatic IRI, concanavalin A (con A) hepatitis and
paracetamol-induced liver injury. These models were interrogated with a
combination of (transgenic and knockout) mouse lines, in vivo antibody depletion
and small molecule inhibition. Injury was evaluated primarily in terms of the
biochemical marker of liver injury alanine aminotransferase (ALT). Data were
correlated with human tissue where possible.
Results
T cells (CD3εKO vs WT p=0.010), but not other lymphocyte populations (B cells, NK
cells, or other innate lymphoid cells), play a central role in warm hepatic IRI.
Programmed Death Receptor-1 (PD-1) is a negative regulator of pro-inflammatory
cytokine production by T cells and the absence of PD-1 was associated with
significantly worse hepatic IRI (p=0.034), con A hepatitis (p=0.00020) and
paracetamol-induced liver injury (p=0.0050). Interferon-γ (IFNγ) and T-box
expressed in T cells (T-bet) are important mediators of hepatic IRI (p=0.017) and
paracetamol induced liver injury (p=0.0007). The absence of IL-6 was associated
with significant protection in paracetamol induced liver injury (p=0.006). The
infiltrates within the recipient liver of patients transplanted following paracetamol
overdose stain positively for PD-1, IFNγ and T-bet. The Janus family of kinases
(JAK) play an important role in the common pathways of cytokine signal
transduction. In vivo use of a selective JAK1/JAK2 inhibitor is protective in hepatic
IRI (p=0.0014), con A hepatitis (p=0.019) and paracetamol-induced liver injury
(p=0.0045).
Conclusions
Common pathways appear to exist in the immune-mediated secondary phase of
injury in ALI. Targeting these pathways will complement existing (cytoprotective)
treatment strategies.