A peptide composed of tandem analogs of two myasthenogenic T cell epitopes interferes with specific autoimmune responses.
Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor alpha-subunit, p195-212 and p259-271, were previously shown to stimulate peripheral blood lymphocytes of patients with MG and were found to be immunodominant T cell epitopes in SJL and BALB/c mice, respectively. Single amino acid substituted analogs of p195-212 (analog Ala-207) and p259-271 (analog Lys-262) were synthesized. We showed that analogs Ala-207 and Lys-262 inhibited, in vitro and in vivo, the proliferative responses of T cell lines specific to the relevant peptide and lymph node cells of mice 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 arranged two single (Ala-207 and Lys-262) analogs (dual analog) either sequentially (Ala-207-Lys-262) or reciprocally (Lys-262-Ala-207). In the present study, we report that both dual analogs could bind to major histocompatibility complex class II molecules on antigen-presenting cells of SJL and BALB/c mice. Analog Lys-262-Ala-207, which bound more efficiently to major histocompatibility complex class II molecules, was found to inhibit the proliferative responses of both p195-212- and p259-271-specific T cell lines. Furthermore, the analog inhibited the in vivo priming of lymph node cells of both SJL and BALB/c mice when administered i.v., i.p., or per os. The dual analog Lys-262-Ala-207 could also immunomodulate myasthenogenic manifestations in mice with experimental autoimmune MG induced by inoculation of a pathogenic T cell line. Thus, a single peptide that is composed of analogs to two epitope specificities can be used to regulate T cell responses and disease associated with each epitope.
Katz-Levy
Y
Y
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Paas-Rozner
M
M
Kirshner
S
S
Dayan
M
M
Zisman
E
E
Fridkin
M
M
Wirguin
I
I
Sela
M
M
Mozes
E
E
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D010446:Peptide Fragments