An altered peptide ligand inhibits the activities of matrix metalloproteinase-9 and phospholipase C, and inhibits T cell interactions with VCAM-1 induced in vivo by a myasthenogenic T cell epitope.
Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, which are sequences of the human acetylcholine receptor, resulted in MG-associated immune responses. A dual altered peptide ligand (APL) composed of the two APLs of the myasthenogenic peptides inhibited, in vitro and in vivo, those responses. This study was aimed at understanding the mechanism(s) underlying the in vivo inhibitory properties of the dual APL. To this end, we analyzed T cells of mice that were immunized with p259-271 for their adhesiveness toward vascular cell adhesion molecule 1, for the activity of their secreted matrix metalloproteinases (MMPs), and for their intracellular phospholipase C (PLC) activity. Immunization with p259-271 triggered the above three activities and in vivo administration of the dual APL inhibited the latter. Thus, treatment of mice with the dual APL interferes with functions required for T cells to migrate and interact with the self-AChR. This is the first indication that very late antigen 4, MMP-9, and PLC are targets for immunomodulation of autoreactive T cells by altered peptide ligands.
Faber-Elmann
A
A
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Grabovsky
V
V
Dayan
M
M
Sela
M
M
Alon
R
R
Mozes
E
E
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009157:Myasthenia Gravis / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D017077:Culture Media, Conditioned; D018984:Epitopes, T-Lymphocyte; D007295:Inositol Phosphates; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D011950:Receptors, Cholinergic; D019010:Vascular Cell Adhesion Molecule-1; D010738:Type C Phospholipases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9