The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes.

Abstract

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T-cell regulated, antibody-mediated diseases. Peptides p195-212 and p259-271 of the human acetylcholine receptor (AChR) alpha-subunit, were previously shown to be immunodominant T cell epitopes in MG patients as well as in SJL and BALB/c mice, respectively. A dual altered peptide ligand (APL) composed of the two single amino acid analogs of the myasthenogenic peptides was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual APL was shown to down-regulate the clinical manifestations of an established EAMG in C57BL/6 mice injected with Torpedo AChR (TAChR). In the present study we attempted the elucidation of the mechanism(s) by which the dual APL down-regulates EAMG-associated responses. It is shown here that the dual APL acts by actively suppressing, in a specific manner, myasthenogenic T cell responses. The active suppression is mediated, at least partially, by the up-regulation of the secretion of TGF-beta following administration of the dual APL. The up-regulated secretion of TGF-beta is accompanied by down-regulation of IFN-gamma and IL-2 [T helper (Th) 1-type cytokine] secretion and by an up-regulation of IL-10 secretion (Th2-type cytokine). Furthermore, the inhibitory effect of the dual APL could be adoptively transferred to p195-212 or TAChR-immunized mice. The down-regulation of IL-2 secretion and the ability of recombinant IL-2 to rescue lymph node cells of mice treated with the dual APL from a state of unresponsiveness suggests that the dual APL acts also, at least partially, by causing the cells to undergo anergy.

• Authors: M Paas-Rozner, M Sela, E Mozes
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 22 Pg. 12642-7 (Oct 23 2001) ISSN: 0027-8424 [Print] United States
• PMID: 11606745 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Interleukin-2
• Peptide Fragments
• Receptors, Cholinergic
• Transforming Growth Factor beta
• Interleukin-4

Topics

• Amino Acid Sequence
• Animals
• Cytokines (biosynthesis)
• Female
• Immunization
• Interleukin-2 (pharmacology)
• Interleukin-4 (physiology)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Myasthenia Gravis (immunology)
• Peptide Fragments (administration & dosage, immunology)
• Receptors, Cholinergic (immunology)
• T-Lymphocytes (drug effects, immunology)
• Torpedo
• Transforming Growth Factor beta (physiology)