A PEPTIDE COMPOSED OF TANDEM ANALOGS OF 2 MYASTHENOGENIC T-CELL EPITOPES INTERFERES WITH SPECIFIC AUTOIMMUNE RESPONSES

Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoim mune disease, Two peptides representing sequences of the human acetylc holine receptor alpha-subunit, p195-212 and p259-271, were previously shown to stimulate peripheral blood lymphocytes of patients with MG an d were found to be immunodominant T cell epitopes in SJL and BALB/c mi ce, respectively, Single amino acid substituted analogs of p195-212 (a nalog Ala-207) and p259-271 (analog Lys-262) were synthesized, we show ed that analogs Ala-207 and Lys-262 inhibited, in vitro and in vivo, t he proliferative responses of T cell lines specific to the relevant pe ptide and lymph node cells of slice immunized to p195-212 and p259-271 , respectively, To inhibit T cell responses to both peptides (p195-212 and p259-271), we synthesized dual analogs composed of the tandemly a rranged two single (Ala-207 and Lys-262) analogs (dual analog) either sequentially (Ala-207-Lys-262) or reciprocally (Lys-262-Ala-207). In t he present study, we report that both dual analogs could bind to major histocompatibility complex class II molecules on antigen-presenting c ells of SJL and BALB/c mice, Analog Lys-262-Ala-207, which bound more efficiently to major histocompatibility complex class II molecules, wa s found to inhibit the proliferative responses of both p195-212- and p 259-271-specific T cell lines, Furthermore, the analog inhibited the i n vivo priming of lymph node cells of both SJL and BALB/c mice when ad ministered i.v., i.p., or per os. The dual analog Lys-262-Ala-207 coul d also immunomodulate myasthenogenic manifestations in mice with exper imental autoimmune MG, induced by inoculation of a pathogenic T cell l iner. Thus, a single peptide that is composed of analogs to two epitop e specificities can he used to regulate T cell responses and disease a ssociated with each epitope.