Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor. We have previously demonstrated a selection bias of CD4+ T cells expressing the Vbeta5.1 T-cell receptor gene in the thymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these cells, severe combined immunodeficiency mice engrafted with MG thymic lymphocytes were treated with anti-Vbeta5.1 antibody. Signs of pathogenicity (eg, acetylcholine receptor loss and complement deposits at the muscle end plates of chimeric mice) were prevented in anti-Vbeta5.1-treated severe combined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodies against acetylcholine receptor. Thymic cells depleted of Vbeta5.1-positive cells in vitro before cell transfer were nonpathogenic, indicating that Vbeta5.1-positive cells are involved in the production of pathogenic autoantibodies. Acetylcholine receptor loss was prevented by Vbeta5.1 targeting in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-Vbeta5.1 antibody involved both the in vivo depletion of Vbeta5.1-expressing cells and an increase in the interferon-gamma/interleukin-4 ratio, pointing to an immune deviation-based mechanism. This demonstration that a selective and specific T-helper cell population is involved in controlling pathogenic autoantibodies in MG holds promise for the treatment of MG.
Aissaoui
A
A
CNRS ESA 8078, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
Klingel-Schmitt
I
I
Couderc
J
J
Chateau
D
D
Romagne
F
F
Jambou
F
F
Vincent
A
A
Levasseur
P
P
Eymard
B
B
Maillot
M C
MC
Galanaud
P
P
Berrih-Aknin
S
S
Cohen-Kaminsky
S
S
D000293:Adolescent; D000328:Adult; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009045:Motor Endplate / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology
D011948:Receptors, Antigen, T-Cell; D011950:Receptors, Cholinergic