The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes.
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.
Paas-Rozner
M
M
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Sela
M
M
Mozes
E
E
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007114:Immunization; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014101:Torpedo; D016212:Transforming Growth Factor beta / Q000502:physiology
D016207:Cytokines; D007376:Interleukin-2; D010446:Peptide Fragments; D011950:Receptors, Cholinergic; D016212:Transforming Growth Factor beta; D015847:Interleukin-4