CD4(-LYMPHOCYTES MEDIATE ISCHEMIA() T)REPERFUSION-INDUCED INFLAMMATORY RESPONSES IN MOUSE-LIVER/

The success of orthotopic liver transplantation is dependent on multip le factors including MHC tissue compatibility and ischemic/reperfusion injury. Ischemic/reperfusion (I/R) injury in the liver occurs in a bi phasic pattern consisting of both acute phase (oxygen free radical med iated) and subacute phase (neutrophil-mediated) damage. Although numer ous studies have given insights into the process of neutrophil recruit ment after I/R injury to the liver, the exact mechanism that initiates this subacute response remains undefined, Using a T cell-deficient mo use model, we present data that suggests that T-lymphocytes are key me diators of subacute neutrophil inflammatory responses in the liver aft er ischemia and reperfusion, To this end, using a partial lobar liver ischemia model, we compared the extent of reperfusion injury between i mmune competent BALB/c and athymic nu/nu mice, Studies evaluating the extent of liver damage as measured by serum transaminases (GPT) demons trate similar acute (3-6 h) post-I/R responses in these two mouse mode ls, In contrast, the subacute phase (16-20 h) of liver injury, as meas ured by both serum GPT levels and percent hepatocellular necrosis, was dramatically reduced in T cell-deficient mice as compared with those with an intact immune system, This reduction in liver injury seen in n u/nu mice was associated with a 10-fold reduction in hepatic neutrophi l infiltration. Adoptive transfer of T cell-enriched splenocytes from immune competent mice was capable of reconstituting the neutrophil-med iated subacute inflammatory response within T cell-deficient nu/nu mic e. Furthermore, in vivo antibody depletion of CD4(+) T-lymphocytes in immune competent mice resulted in a reduction of subacute phase injury and inflammation as measured by serum GPT levels and neutrophil infil tration, In contrast, depletion of CD8(+) T-lymphocytes had no effect on these indexes of subacute inflammation. Kinetic analysis of T cell infiltration in the livers of BALB/c mice demonstrated a fivefold incr ease in the number of hepatic CD4(+) T-lymphocytes within the first ho ur of reperfusion with no significant change in the number of CD8(+) T -lymphocytes. In summary, these results implicate CD4(+) T-lymphocytes as key regulators in initiating I/R-induced inflammatory responses in the liver, Such findings have implications for therapy directed at th e early events in this inflammatory cascade that may prove useful in l iver transplantation.