Role of activated CD8+ T cells in the initiation and continuation of hepatic damage.

The cause of alcoholic liver disease (ALD) is multifactorial and poorly understood. It is clear that alcohol alone is not responsible for most of the changes associated with ALD and that cofactors are involved in initiation and production of ALD. One cofactor that has received a great deal of attention recently is the concomitant infection with hepatitis C virus (HCV) and alcohol abuse. The interactive effects of HCV and alcohol abuse are still unclear, but apparently they are the result of an inability of the immune system to control the viral infection and exaggerated hepatocyte damage mediated by either the cells of the inflammatory response or factors produced by the inflammatory cells. This review will focus on one aspect of the possible pathogenic effects associated with alcohol abuse and HCV infection: the possible role of the immune system, notably the cytotoxic T lymphocyte (CTL) response. It is clear that the development of a CTL response is critical for the control of HCV infections, and it is also likely that this response is involved in liver damage. In this review, the evidence that shows the importance of the CD8(+) CTL in viral clearance and the role for pathogenesis will be presented. Findings obtained from animal studies that support the suggestion that activated CD8(+) CTLs can induce liver damage will be presented, as will results of recent studies from my laboratory that provide evidence for an effect of alcohol to enhance the liver damage mediated by activated CD8(+) T cells.