The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes

Myasthenia gravis (MIG) and experimental autoimmune MG (EAMG) are T-cell re gulated, anti body-mediated diseases. Peptides p195-212 and p259-271 of the human acetylcholine receptor (AChR) alpha -subunit, were previously shown to be immunodominant T cell epitopes in MG patients as well as in SJL and B ALB/c mice, respectively. A dual altered peptide ligand (APL) composed of t he two single amino acid analogs of the myasthenogenic peptides was shown t o inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthe rmore, the dual APL was shown to downregulate the clinical manifestations o f an established EAMG in C57BL/6 mice injected with Torpedo AChR (TAChR). I n the present study we attempted the elucidation of the mechanism(s) by whi ch the dual APL down-regulates EAMG-associated responses. It is shown here that the dual APIL acts by actively suppressing, in a specific manner, myas thenogenic T cell responses. The active suppression is mediated, at least p artially, by the up-regulation of the secretion of TGF-beta following admin istration of the dual APL. The up-regulated secretion of TGF-beta is accomp anied by down-regulation of IFN-gamma and IL-2 [T helper (Th) 1-type cytoki ne] secretion and by an up-regulation of IL-10 secretion (Th2-type cytokine ). Furthermore, the inhibitory effect of the dual APIL could be adoptively transferred to p195-212 or TAChR-immunized mice. The downregulation of IL-2 secretion and the ability of recombinant IL-2 to rescue lymph node cells o f mice treated with the dual APL from a state of unresponsiveness suggests that the dual APL acts also, at least partially, by causing the cells to un dergo anergy.