title: Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.
abstract: 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.
authors.affiliation: CNRS ESA 8078, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: A
authors.initials: A
authors.lastname: Aissaoui
authors.forename: I
authors.initials: I
authors.lastname: Klingel-Schmitt
authors.forename: J
authors.initials: J
authors.lastname: Couderc
authors.forename: D
authors.initials: D
authors.lastname: Chateau
authors.forename: F
authors.initials: F
authors.lastname: Romagne
authors.forename: F
authors.initials: F
authors.lastname: Jambou
authors.forename: A
authors.initials: A
authors.lastname: Vincent
authors.forename: P
authors.initials: P
authors.lastname: Levasseur
authors.forename: B
authors.initials: B
authors.lastname: Eymard
authors.forename: M C
authors.initials: MC
authors.lastname: Maillot
authors.forename: P
authors.initials: P
authors.lastname: Galanaud
authors.forename: S
authors.initials: S
authors.lastname: Berrih-Aknin
authors.forename: S
authors.initials: S
authors.lastname: Cohen-Kaminsky
mesh_terms: 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
chemical_list: D011948:Receptors, Antigen, T-Cell; D011950:Receptors, Cholinergic