Role of intercellular adhesion molecule-1 and lymphocyte function–associated antigen-1 during nonsuppurative destructive cholangitis in a mouse graft-versus-host disease model



Intercellular adhesion molecule-1(ICAM-1) is expressed abnormally on the bile duct epithelium during the course of primary biliary cirrhosis (PBC), but the importance of ICAM-1 and its lymphocyte function-associated antigen-1 (LFA-1) receptor during the course of nonsuppurative destructive cholangitis (NSDC) has not been defined. To address this question, we defined the relationship between ICAM-1 on the intrahepatic bile duct epithelium and the evolution of NSDC lesions in a mouse graft-versus-host disease (GVHD) model. We also determined the effects of anti–ICAM-1 and anti–LFA-1 treatments on NSDC, intrahepatic lymphokine production, and the homing of lymphocytes to the livers of GVHD mice. ICAM-1 was initially detected on the bile duct epithelium and portal vein endothelium on day 7 of GVHD. There was a significant positive correlation between the intensity of ICAM-1 staining and histological bile duct damage (r = .58, P < .05) between day 3 and 28. Treatment with anti–ICAM-1 (but not anti–LFA-1) decreased both the mean grades of portal inflammation (P = .003) and NSDC (P = .002) lesions compared with control immunoglobulin G (IgG) treatments. Combined treatment with anti–ICAM-1 and anti–LFA-1 caused a further decrease in the amount of portal inflammation and bile duct damage compared with anti–ICAM-1, alone (P = .02). Anti–ICAM-1 treatment also decreased both the percentage of T cells and the production of interleukin-2 (IL-2) and IL-12 in the liver (P < .01), but had no effect on IL-4, IL-10, and interferon gamma. Neither anti–ICAM-1 nor anti–LFA-1 prevented lymphocytes from homing to the liver. These results indicate that both ICAM-1 and LFA-1 are important to the pathogenesis of NSDC