Suppression of hepatic lesions in a murine graft-versus-host reaction by antibodies against adhesion molecules

Background/Aims: The injection of parental CD4(+) T cells into major histocompatibility complex (MHC) class II disparate F-1 hybrid mice induced an autoimmune graft-versus-host reaction (GVHR) which is analogous to autoimmune liver diseases. The interaction of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) has been known to be profoundly involved in the trafficking of lymphocytes into the inflammatory tissues. The aim of this study was to clarify the role of VLA-4 or VCAM-1 in the development of GVHR-induced hepatic lesions in our model. Methods: B6 T spleen cells were injected into (B6.C-H-2(bml2)xB6) F-1 mice intravenously, Anti-VLA-4 mAbs and/or anti-VCAM-1 mAbs were injected intraperitoneally at a dose of 2.5 mg/kg of each mAbs per body weight of mouse, We examined the changes in GVHR-induced hepatic lesions, serum levels of antimitochondrial antibodies (AMA) and cytokine mRNA expressions of liver-infiltrating lymphocytes using H.E. and immunohistochemical staining, enzyme-linked immuno-sorbent assay (ELISA), and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Results: Hepatic lesions of anti-VLA-4 mAbs-treated mice were inhibited compared with those of GVHR mice. However, the administration of mAbs did not interfere with the induction of splenomegaly, the invasion of CD4(+), CD8(+), B220(+), or Mac-1(+) cells around bile ducts, nor the production of AMA, Liver-infiltrating CD4(+) T cells obtained from these treated mice did not alter the expression of T helper (Th)1 and Th2 cytokine mRNA. Conclusion: The results suggest that treatment with antibodies against these adhesion molecules could inhibit the infiltration of lymphocytes without affecting the Th1/Th2 balance, The blockade of VLA-4-mediated cell infiltration into the liver in this model may have a possible novel therapeutic role of VLA-4 mAbs.