TREATMENT OF IMMUNE CELL-MEDIATED LIVER-DAMAGE BY NONPEPTIDIC MIMETICS OF THE EXTRACELLULAR MATRIX-ASSOCIATED ARG-GLY-ASP EPITOPE

The etiology of T-cell-mediated liver injury involves the migration of immune cells, notably CD4(+) T lymphocytes, into liver tissues. This process is mediated primarily by integrin-recognition of the sub-endothhelium basement membranes and the extracellular matrix. The Arg-Gly-Asp-containing peptide, a major cell-adhesive ligand of extracellular matrix, is present in various plasma- and matrix-glycoproteins, such as fibronectin. Recently, we have described the design and usage of nonpeptide mimetics of Arg-Gly-Asp which bind specifically to integrins, and thereby, inhibit T cell immunity in vivo, We examined the efficacy of Arg-Gly-Asp-mimetics as potential therapeutic compounds for the treatment of experimental T-cell-mediated liver injury induced in mice by injection of Concanavalin-A. We now report that the Arg-Gly-Asp-mimetics specifically inhibited the binding of murine T cells to fibronectin, but did not affect the proliferative response of these cells in vitro. Intraperitoneal or oral administration of the Arg-Gly-Asp-mimetics but not the Arg-Gly-Asp-containing peptide, inhibited liver damage in mice if given before their inoculation with Con-A, as manifested by a lesser elevation in their serum levels of hepatic enzymes. The inhibitory effect of the Arg-Gly-Asp-mimetics was dose-dependent, the ED(50) of the tested molecules being in the range of 100 pg per mouse and reaching maximal effect, e.g. similar to 95% inhibition, at 500 pg per mice. Thus, the Arg-Gly-Asp-mimetics described here may be used therapeutically to prevent immune-cell-mediated acute or chronic pathological reactions in the liver.