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-endothelium 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 ED50 of the tested molecules being in the range of 100 micrograms per mouse and reaching maximal effect, e.g. approximately 95% inhibition, at 500 micrograms 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.
Hershkoviz
R
R
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Lider
O
O
Bruck
R
R
Aeed
H
H
Greenspoon
N
N
Halpern
Z
Z
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D000939:Epitopes; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins; D006146:Guanidines / Q000494:pharmacology; D007111:Immunity, Cellular; D007797:Laminin; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology; D014631:Valerates / Q000494:pharmacology
D000939:Epitopes; D005353:Fibronectins; D006146:Guanidines; D007797:Laminin; D009842:Oligopeptides; D011971:Receptors, Immunologic; D014631:Valerates; D003208:Concanavalin A; C084660:SF 6,5; C047981:arginyl-glycyl-aspartic acid