Oral administration of a dual analog of two myasthenogenic T cell epitopesdown-regulates experimental autoimmune myasthenia gravis in mice

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-reg ulated, antibody-mediated autoimmune diseases. The major autoantigen in MG is the nicotinic acetylcholine receptor (AChR), Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, were prev iously shown to be immunodominant T cell epitopes in MG patients as well as , respectively, in SJL and BALB/c mice. A dual analog (termed Lys-262-Ala-2 07) composed of the tandemly arranged two single amino acid analogs of p195 -212 and p259-271 was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual analog could down-regulate mya sthenogenic manifestations in mice with EAMG that was induced by inoculatio n of a pathogenic T cell line. In the present study, the ability of the dua l analog to treat EAMG induced in susceptible C57BL/6 mice by native Torped o AChR was evaluated. Mice that were diagnosed to have clinical symptoms of EAMG were treated with the dual analog by oral administration, 500 mu g pe r mouse three times a week for 5-8 weeks, Treatment with the dual analog do wn-regulated the clinical manifestations of the ongoing disease as assessed by the clinical score, grip strength (measured by a grip strength meter), and electromyography. The effects on the clinical EAMG correlated with a re duced production of anti-AChR antibody as well as a decrease in the secreti on of interleukin-2 and, more dramatically, interferon-gamma, in response t o AChR triggering. Thus, the dual analog is an efficient immunomodulator of EAMG in mice and might be of specific therapeutic potential for MG.