Specific tolerance to an acetylcholine receptor epitope induced in vitro in myasthenia gravis CD4+ lymphocytes by soluble major histocompatibility complex class II-peptide complexes.
In autoimmune disorders, inactivation of pathogenic antigen-specific T cells, rather than global immunosuppression, would be highly desirable. One way to achieve this would be to deliver the first antigen-specific signal to the T cell in the absence of the second costimulatory signal. Myasthenia gravis (MG) is a well-characterized autoimmune disease in which T cell-dependent autoantibodies are directed against the acetylcholine receptor (A ChR) at the neuromuscular junction. AChR-specific T cells have been cloned from MG patients, and in this study, we have induced long-lasting tolerance in vitro in one particular clone (PM-A1) with a known peptide epitope (alpha 144-163) and MHC class II restriction (DR4 Dw14.2 or 4.2) by using soluble MHC-class II peptide complexes. Preincubation of PM-A1 T cells with such complexes induced death by apoptosis in < or = 40-50% of the AChR-specific cells. Surviving cells remained refractory to stimulation with AChR-derived synthetic peptides or recombinant polypeptides for < or = 38 d after complex treatment. These effects were highly specific, dose-dependent and required > 2 h preincubation. The T cells could be protected from the tolerizing effects of complex by coincubation with DR-matched or -mismatched antigen-presenting cells. This work shows that antigen-specific T cells can be selectively killed or anergized using soluble MHC class II: peptide complexes. Such an antigen-specific therapy offers a rational approach to the immunotherapy of autoimmune or allergic disease in vivo.
Nicolle
M W
MW
Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
Nag
B
B
Sharma
S D
SD
Willcox
N
N
Vincent
A
A
Ferguson
D J
DJ
Newsom-Davis
J
J
D000293:Adolescent; D000938:Antigen-Presenting Cells / Q000502:physiology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D009157:Myasthenia Gravis / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*
D000939:Epitopes; D006684:HLA-DR Antigens; D011950:Receptors, Cholinergic