Despite the generally accepted knowledge that intermediate metabolic products liberated from injured hepatic cells cause serious autoimmune disease, some patient-=_ suffering from fulminating hepatitis revovers completely without proceeding to chronic hepatitis nor inducing cirrhotic changes. The fact may suggest that acutely damaged liver cells liberate both immunosuppressive factor and the factor inhibiting fibroblast proliferation which enables complete recovery by preventing sensitization to the intermediate metabolic products from injured hepatic cells and also preventing fibrotic _ changes of the liver tissue.
In chronic damage, however, those protecting liver factors decrease so that both autoimmune disease and cirrhosis are induced.
A series of animal experiment using LEW mice was carried out to back up these postulation.
Acute hepatic injury was induced by dimethyl nitrosamine (DMNA: 35mg/kg B.W. intravenously). Chronic injury was produced with carbon tetrachloride (CCl4: lml/kg B.W. intramuscularly, b.i.w.) for 2-4 weeks and then progressed to liver cirrhosis by farther administration until 5-10 weeks. Sera and liver factors (LF) were prepared from the animals and used for inhibition tests of fibroblast proliferation and MLC reaction.
Furthermore, cell-count and subpopulation of the thymus cell were done by monoclonal antibodies (W3/25, OX-S).
LF of untreated (control) and DMNA-treated animals exhibited very strong unspecific inhibition effects of fibroblast proliferation and allogenic stimulation. However, with progression of hepatic damage (chronic hepatitis and cirrhosis) both suppressive abilities gradually reduced.
Normal sera showed only slight inhibition of allogenic stimulation but sera of animals with acute hepatic damage showed very strong inhibition. In the 2 weeks of CC1, treatment, the inhibitory ability was about 40% and with progression of hepatic damage, it gradually reduce. Normal sera of animals with chronic hepatic damage could not suppress the fibroblast proliferation while sera of acute hepatic damage inhibited it very strongly.
With chronic hepatic damage, the thymus gradually atrophied and after 10 weeks
of CCL treatment the atrophy was complete. Thymocytes differentiation was found only in the animals with acute hepatic damage suggesting that immunosuppressive factors liberated from the acutely damaged hepatocytes caused differentiation of the thymocytes.
|