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 p259-2 71, 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 v ivo, 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 a dhesiveness toward vascular cell adhesion molecule 1, for the activity of t heir secreted matrix metalloproteinases (MMPs), and for their intracellular phospholipase C (PLC) activity. Immunization with p259-271 triggered the a bove three activities and in vivo administration of the dual APL inhibited the latter. Thus, treatment of mice with the dual APL interferes with funct ions 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 target s for immunomodulation of autoreactive T cells by altered peptide ligands.