ALTERED T-LYMPHOCYTE RESPONSIVENESS TO POLYCLONAL CELL ACTIVATORS IS RESPONSIBLE FOR LIVER-CELL NECROSIS IN ALCOHOL-FED RATS

The role of T-cell activation in alcoholic liver disease was investiga ted in rats fed alcohol and subsequently exposed to concanavalin A (Co n A). Following Con A injection (20 mg/kg body weight), greater increa ses in liver-to-body weight ratio and ALT levels were observed at 12 a nd 24 hr in rats fed ethanol, compared with control rats fed sucrose. Furthermore, increases in serum interleukin-6 and tumor necrosis facto r-alpha levels were noted in ethanol-fed rats, with maximal levels det ected at 4 hr declining thereafter, but remaining above control levels at 24 hr. Analysis of T-cell subpopulations showed an increased perce ntage of CD4(+), CD5(+), and CD8(+) T cells in blood from all groups, but not in liver perfusate. In contrast, a significant increase in the percentage of activated CD25(+) T cells was detected in both blood an d liver perfusate from rats fed ethanol even 24 hr after Con A injecti on. When CD4(+) and CD8(+) T cells from liver perfusate were cultured in the absence or presence of Con A, an increase in interleukin-6 and tumor necrosis factor-alpha production in supernatants was observed in ethanol-fed rats. In cultures stimulated with Con A, a 2- to 8-fold i ncrease in cytokine production was detected, with intrahepatic CD4(+) T cells being the major source. Immunohistological analysis revealed i nfiltration of CD4(+) T cells around portal vein and central vein area s associated with fatty liver and severe hepatic necrosis. The results suggest that alcohol consumption induced a dysregulated T-cell popula tion that mediated hepatic necrosis following polyclonal activation wi th Con A.