In this model, passenger leukocytes, which are donor-derived hepatic resident leukocytes, appear to mediate much of the injury. CD39tg livers were more resistant to IRI and were deficient in both CD4+ T cells and iNKT cells. Reconstitution of these livers with a WT immune system (restoring resident T-cell number and function) abolished resistance. Furthermore, WT donor livers depleted of CD4+ T cell showed similar protection
to CD39tg donor livers. Although CD4+ iNKT cells represent 20% to 40% of hepatic T cells,27 conventional click here CD4+ T cells appeared to be the prime orchestrators of early hepatic injury, as livers from iNKT KO mice were not protected. The role of CD4+ T-cell subsets in warm hepatic IRI has been defined.28 T-cell activation occurring through antigen-dependent and -independent mechanisms mediates liver injury through neutrophil recruitment and activation.
Further, NKT cell activation can cause direct liver injury in partial hepatic warm IRI.28 Our data are in accordance with recent observations in a similar mouse liver transplantation model using CD1d KO donors and WT recipients,29 but is at odds with data from a warm model of hepatic IRI where systemic blocking of NKT cells was protective and adoptive transfer of NKT cells in T-cell-deficient mice restored injury.14 This discrepancy suggests that warm and cold IRI have two distinct pathophysiologies and that the immune Selleck BMS-354825 response against the transplanted organ differs from the response to local ischemia. Further, NK and NKT cells mediate phase-specific responses in IRI: depletion of NK1.1 cells, which encompass both NK and NKT cells, failed to moderate
IRI at early timepoints17 but significantly reduced later hepatocellular damage.14 NK and NKT cells are a prime source of IFN-γ, which becomes critically important at 24 hours of reperfusion. Our data confirm selleck products that CD4+ iNKT cells of donor origin have minimal effect during the early phase (within 6 hours) of IRI. We have previously shown that the overexpression of CD39 on the renal parenchyma mitigates IRI up to 72 hours following transplantation.15 However, overexpression of CD39 within the hepatic parenchyma appears to play a minor role, if any, in this model of liver transplantation. Recipient circulating T cells, particularly CD4+ T cells, are recruited to the liver within hours of perfusion.16 It was anticipated that the adenosine-rich milieu created by CD39 overexpression would modify the inflammatory response. However, there was no significant difference in the susceptibility to IRI of WT or CD39tg donor livers following reconstitution with WT bone marrow, suggesting minimal if any effect of tissue restricted overexpression of CD39. This was unexpected, given the potent antiinflammatory effects of adenosine, but may be accounted for by the very short half-life of adenosine in the circulation.