EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION ON IMMUNOGENICITY OF MURINE LIVER-CELLS IN MICE

Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been implicated in the pathogenesis of various inflammatory liver disease states, includ ing viral and autoimmune hepatitis as well as liver allograft rejectio n. Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine known to up-regulate adhesion molecules as well as major histocompati bility complex (MHC) class I expression, and has been demonstrated to be important in the rejection of vascularized organ allografts. The cu rrent studies address the effect of TNF-alpha and the role of ICAM-1 e xpression on liver cell immunogenicity in vitro in mixed lymphocyte he patocyte culture (MLHC), in vitro in mixed lymphocyte liver nonparench ymal cell culture (MLNPC), in vivo in hepatocyte sponge matrix allogra fts (HC-SMA), and in vivo in liver nonparenchymal cell sponge matrix a llografts (NPC-SMA). Purified allogeneic hepatocytes (HC) and liver no nparenchymal cells (NPC) under naive, unstimulated conditions demonstr ated different profiles of MHC antigen and adhesion molecule expressio n, but both liver cell populations stimulated the proliferation and de velopment of allospecific cytotoxic effecters in vitro and in vivo. De spite significant up-regulation of MHC class I and ICAM-1 on both HC a nd liver NPCs by in vivo treatment with TNF-alpha, the immunogenicity of TNF-alpha-stimulated liver cells was not appreciably different from naive, unstimulated liver cells. In contrast, ICAM-1-negative HC and NPCs were significantly less immunogenic both in terms of lymphocyte p roliferative responses and the generation of allospecific cytolytic ef fecters. These results suggest that constitutive expression of ICAM-1 enhances the immunogenicity of ''donor'' liver cells but is not absolu tely required to elicit immune responses to allogeneic liver cells. Fu rther studies to determine the role of adhesion molecule expression on trafficking of host immune cells to the liver and the role of adhesio n molecule expression by host cells are required to clarify their role in immune responses to liver cells.