Prevention of experimental myasthenia gravis by nasal administration of synthetic acetylcholine receptor T epitope sequences.
T cell tolerization prevents and improves T cell-mediated experimental autoimmune diseases. We investigated here whether similar approaches could be used for antibody (Ab)-mediated autoimmune diseases. Myasthenia gravis, caused by IgG Ab against muscle acetylcholine receptor (AChR), is perhaps the best characterized of them. We used an animal model, experimental myasthenia gravis induced in C57Bl/6 mice by immunization with Torpedo acetylcholine receptor (TAChR), to demonstrate that nasal administration of synthetic sequences of the TAChR alpha-subunit- forming epitopes recognized by anti-TAChR CD4+ T helper cells (residues alpha150-169, alpha181-200, and alpha360-378), given before and during immunization with TAChR, causes decreased CD4+ responsiveness to those epitopes and to TAChR, reduced synthesis of anti-TAChR Ab, and prevented experimental myasthenia gravis. These effects were not induced by nasal administration of synthetic epitopes of diphtheria toxin. Secretion of IL-2, IL-4, and IL-10 by spleen T cells from TAChR immunized mice, in response to challenge with TAChR in vitro, indicated that in sham-tolerized mice only Th1 cells responded to TAChR, while peptide-treated mice had also an AChR-specific Th2 response. The TAChR peptide treatment induced also in vitro anergy to the TAChR of the spleen T cells, which was reversed by IL-2.
Karachunski
P I
PI
Department of Biochemistry, College of Biological Sciences, University of Minnesota, St. Paul, Minnesota 55108, USA.
Ostlie
N S
NS
Okita
D K
DK
Conti-Fine
B M
BM
D000281:Administration, Intranasal; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004167:Diphtheria Toxin / Q000138:chemical synthesis / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009157:Myasthenia Gravis / Q000276:immunology / Q000517:prevention & control*; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology*; D012137:Respiratory System / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology; D014101:Torpedo; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology*
D000906:Antibodies; D004167:Diphtheria Toxin; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D010455:Peptides; D011950:Receptors, Cholinergic; D014614:Vaccines, Synthetic