INDUCTION AND PERSISTENCE OF IMMUNE-MEDIATED CHOLANGIOHEPATITIS IN NEONATALLY THYMECTOMIZED MICE

The availability of recombinant autoantigens allows the experimental s tudy of the relationships between primary biliary cirrhosis (PBC) and mitochondrial antigens. We took advantage of these recombinant autoant igens and attempted to induce autoimmune cholangitis by immunizing neo natally thymectomized (NTx) lipopolysaccharide (LPS)-treated A/J mice, known to be prone to organ-specific autoimmune diseases. We employed a recombinant protein containing a dual-headed molecule that coexpress es the immunodominant epitope of the E2 subunits of the pyruvate dehyd rogenase complex and the branched-chain ketoacid dehydrogenase complex . We report herein that an immune-mediated cholangiohepatitis was indu ced by such immunization and the concurrent injection of LPS into NTx mice. The incidence of cholangitis was 79% in the NTx, immunized, LPS group compared to 14% in the NTx, nonimmunized, LPS group. The histopa thology ranged from mild to severe and included bile duct damage, foca l hepatic necrosis, and endotheliitis, but no granulomas. Moreover, al most all such lesions persisted for 12 weeks after the discontinuation of immunization and LPS injections in the NTx mice. Interestingly, we were successful (89%) in transferring the cholangiohepatitis by injec tion of liver infiltrating mononuclear cells from the NTx, immunized, LPS mice into congenic nonimmunized NTx mice; such lesions could not b e transferred with spleen cells. Although the pathology is not typical of PBC, this model offers a unique venue for the study of immune-medi ated hepatobiliary injury, (C) 1998 Academic Press.