Immunological studies on the drug-induced allergic hepatitis

The possible involvement of cell-mediated immunity in the pathogenesis of drug-induced allergic hepatitis was investigated in 21 patients; 6 patients with cholestasis, two cases with the hepatitis resembling viral hepatitis and 13 cholestatic hepatitis. The peripheral blood lymphocytes from all these patients showed the positive lymphocyte transformation and MIF production when stimulated by the offending drug in the presence of liver specific lipoprotein. By injection of the culture medium prepared from activated lymphocytes into mesenteric vein of rat, a marked reduction of bile flow and bile acid secretion was observed in 12 cases among 17 patients tested. Active material which caused the reduction of bile flow was fractionated by a gel filtration and was identified to have similar molecular size to MIF. Morphologically, a dilated bile canaliculus with diminution of microvilli and vesicles around the dilated bile canaliculus were observed by an electron microscopy after injection of culture supernatant or their fractionated material into mesenteric vein of rat. No such changes could be seen in rats by administering the supernatant of lymphocytes from normal individuals prepared as above. Macrophage activating factor (MAF), a kind of lymphokines, was also detected in the culture medium of activated lymphocytes from seven patients among eight cases tested. The MAF-activated macrophages were shown to exhibit a cytotoxic effect on the separated liver cells by judging from the inhibition of albumin biosynthesis. Moreover, the antibody-dependent cell-mediated cytotoxic reaction as well as lymphocyte-mediated cytotoxicity were also demonstrated in three cases among nine patients tested. These observations suggest that diverse immune reactions were possible correlated to the pathogenesis of the drug-induced allergic hepatitis although their exact participation or relative significances are remained to be elucidated.