title: Suppression of hepatic lesions in a murine graft-versus-host reaction by antibodies against adhesion molecules.
abstract: OBJECTIVE
  The injection of parental CD4+ T cells into major histocompatibility complex (MHC) class II disparate F1 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 VLA4 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-2bm12xB6) F1 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 immunosorbent 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Itoh
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: R
authors.initials: R
authors.lastname: Unno
authors.forename: T
authors.initials: T
authors.lastname: Ikegami
authors.forename: J
authors.initials: J
authors.lastname: Shoda
authors.forename: M
authors.initials: M
authors.lastname: Doy
authors.forename: M
authors.initials: M
authors.lastname: Fujiwara
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D003602:Cytotoxicity, Immunologic; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*
chemical_list: D000906:Antibodies; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1