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 α -subunit, p195-212 and p259-271, were previously shown to stimulate peripheral blood lymphocytes of patients with MG and were found to be immu...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (7), p.3200-3205
Main Authors: Katz-Levy, Yael, Paas-Rozner, Miri, Kirshner, Susan, Dayan, Molly, Zisman, Einat, Fridkin, Mati, Wirguin, Itzhak, Sela, Michael, Mozes, Edna
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antigen presenting cells
Antigen-Presenting Cells - immunology
Autoimmune diseases
Biological Sciences
Cell lines
Cells
Cellular biology
Cellular immunity
Epitopes
Epitopes - chemistry
Epitopes - immunology
Humans
Immunity (Disease)
Inoculation
Lymph nodes
Mice
Mice, Inbred Strains
Molecular Sequence Data
Myasthenia gravis
Myasthenia Gravis - immunology
Peptide Fragments - chemistry
Peptide Fragments - immunology
Peptides
Spleen cells
T lymphocytes
T-Lymphocytes - immunology
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Summary:Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor α -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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.7.3200