Role of Intercellular Adhesion Molecule–1 and Lymphocyte Function-Associated Antigen–1 During Nonsuppurative Destructive Cholangitis in A Mouse Graft–Versus–Host Disease Model

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Abstract
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