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 musc le acetylcholine receptor. We have previously demonstrated a selection bias of CD4(+) T cells expressing the V beta 5.1 T-cell receptor gene in the th ymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these ce lls, severe combined immunodeficiency mice engrafted with MG thymic lymphoc ytes were treated with anti-V beta 5.1 antibody. Signs of pathogenicity (eg , acetylcholine receptor loss and complement deposits at the muscle end pla tes of chimeric mice) were prevented in anti-V beta 5.1-treated severe comb ined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodie s against acetylcholine receptor. Thymic cells depleted of V beta 5.1-posit ive cells in vitro before cell transfer were nonpathogenic, indicating that V beta 5.1-positive cells are involved in the production of pathogenic aut oantibodies. Acetylcholine receptor loss was prevented by V beta 5.1 target ing in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-V beta 5.1 antibody involved both the in vivo depletion of V beta 5.1-expressing cells and an increase in the inter feron-gamma/interleukin-4 ratio, pointing to an immune deviation-based mech anism. This demonstration that a selective and specific T-helper cell popul ation is involved in controlling pathogenic autoantibodies in MG holds prom ise for the treatment of MG.