Enhanced expression of cytokine-induced neutrophil chemoattractant in rat hepatic allografts during acute rejection

Abstract

The kinetics of messenger RNA (mRNA) and protein levels of cytokine-induced neutrophil chemoattractant (CINC) in rat hepatic allografts during acute rejection were investigated. Infiltrating cells were identified by double immunostaining with anti-CINC and anti-macrophage monoclonal antibodies, ED1 and ED2. The serum CINC concentration in untreated hepatic allograft recipients increased significantly at a constant rate over time after transplantation. No significant increases in serum CINC concentrations were observed in hepatic isografts or allografts treated with the immunosuppressant FK506. The number of neutrophils in untreated hepatic allografts increased significantly at a constant rate. Conversely, neutrophil accumulation in isografts or allografts treated with FK506 was much less than in untreated hepaticallografts. Immunostaining revealed that in the portal areas, mononuclear cells infiltrating untreated allograft liver were mainly positive for CINC and that CINC+ cells represented a subpopulation (approximately 25%) of the ED1+ cells. On the other hand, in the sinusoidal areas CINC+ cells were scattered and mainly positive for ED2. Levels of CINC mRNA in liver tissues taken from untreated hepatic allografts increased after transplantation, peaked on day 5, and decreased thereafter. Hepatic allografts treated with FK506 or isografts showed much lower levels of CINC mRNA than untreated allografts. Allogeneic mixed lymphocyte reactions induced CINC production. The cellular source of CINC was mononuclear cells. CINC production in mixed lymphocyte reactions was inhibited in the presence of anti-tumor necrosis factor alpha (TNF-alpha) antibody. These results suggest that enhanced expression of CINC mRNA and prominent accumulation of neutrophils in the liver grafts are characteristic features of the immune response during acute rejection.

Octreotide regulates CC but not CXC LPS‐induced chemokine secretion in rat Kupffer cells

“…Chemokine expression in the liver is induced in almost all types of pathological conditions, and a correlation exists between chemokines released and the predominant leukocyte population infiltrating the liver (Marra, 2002). Overexpression of the CXC chemokines IL‐8 and CINC in the hepatic tissue has been associated with the neutrophilic infiltration and the degree of tissue inflammation observed in acute alcoholic hepatitis, viral hepatitis, cirrhosis, and experimental models of liver allograft rejection ( Sheron et al , 1993 ; Yamaguchi et al , 1997 ; Shimoda et al , 1998 ; Polyak et al , 2001 ). MIP‐2 and KC have been implicated in the development of ischaemia–reperfusion liver injury, and neutralization of these molecules reduced neutrophilic infiltration and hepatocellular damage ( Lentsch et al , 1998 ).…”

Sequential analysis of donor-specific antibodies and pathological findings in acute antibody-mediated rejection in a rat renal transplantation model

“…54 ICAM-1 is one of the adhesion molecules that is present on endothelial cells, and some experiments have demonstrated that upregulation or induction of ICAM-1 is dependent on stimulation with cytokines such as TNF-a and IL-1b. 55,56 Surface expression of ICAM-1 did not increase soon after transplantation, but increased gradually during the late phase.…”

The role of chemokines in the immunopathology of the liver

“…After day 5 post-transplant, however, CINC levels began to decrease. Other data suggest that decreasing IL-8 is a consequence of immunosuppression, since rats treated with FK506 typically have much lower liver IL-8 levels than their untreated controls (51). Thus, IL-8 may play a role in acute rejection of liver transplants related to the infiltration of leukocytes.…”