Peptide analogs to pathogenic epitopes of the human acetylcholine receptor a subunit as potential modulators of myasthenia gravis

Einat Zisman*, Yael Katz-Levy, Molly Dayan, Susan L. Kirshner, Miri Paas-Rozner, Arnon Karni, Oded Abramskyi, Chaim Brautbar, Mati Fridkin, Michael Sela, Edna Mozes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Myasthenia gravis is an autoimmune disease in which T cells specific to epitopes of the autoantigen, the human acetylcholine receptor, play a role. We identified two peptides, p195-212 and p259-271, from the a subunit of the receptor, which bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) from peripheral blood lymphocytes of myasthenia gravis patients and stimulated lymphocytes of >80% of the patients. We have prepared analogs of these myasthenogenic peptides and tested their ability to bind to MHC class II determinants and to interfere specifically with T-cell stimulation. We first determined relative binding efficiency of the myasthenogenic peptides and their analogs to APCs of patients. We found that single substituted analogs of p195-212 (Ala-207) and p559-271 (Lys-262) could bind to human MHC molecules on APCs as efficiently as the original peptides. Moreover, dual analogs containing the two single substituted analogs in one stretch (either sequentially, Ala-207/Lys-262, or reciprocally, Lys-262/Ala-207) could also bind to APCs of patients, including those that failed to bind one of the single substituted analogs. The single substituted analogs significantly inhibited T-cell stimulation induced by their respective myasthenogenic peptides in >95% of the patients. The dual analogs were capable of inhibiting stimulation induced by either of the peptides: They inhibited the response to p195-212 and p259-271 in >95% and >90% of the patients, respectively. Thus, the dual analogs are good candidates for inhibition of T-cell responses of myasthenia gravis patients and might have therapeutic potential.

Original languageEnglish
Pages (from-to)4492-4497
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number9
DOIs
StatePublished - 30 Apr 1996
Externally publishedYes

Keywords

  • Altered peptide ligand
  • Binding to major histocompatibility complex class II
  • Immunotherapy
  • Peptide antagonists

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