Antigen-specific modulation of experimental myasthenia gravis: nasal tolerization with recombinant fragments of the human acetylcholine receptor alpha-subunit.
Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AcChoR) is the major autoantigen. The immune response in these diseases is heterogeneous and is directed to a wide variety of T and B cell epitopes of AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore, have a broad specificity. We used recombinant fragments of the human AcChoR, encompassing the extracellular domain of the alpha-subunit, or shorter fragments derived from it, in experiments to modulate EAMG. We have demonstrated that intranasal administration of these recombinant fragments, which represent a major portion of epitopes involved in MG, prevents the induction of EAMG in rats and immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight loss, and muscle AcChoR content. These effects on EAMG were accompanied by a marked reduction in the proliferative T-cell response and IL-2 production in response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal tolerance induced by appropriate recombinant fragments of human AcChoR is effective in suppressing EAMG and might possibly be considered as a therapeutic modality for MG.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
D
D
Barchan
M C
MC
Souroujon
S H
SH
Im
C
C
Antozzi
S
S
Fuchs
D000281:Administration, Intranasal; D000818:Animals; D004195:Disease Models, Animal; D004557:Electric Organ / Q000502:physiology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood; D007132:Immunoglobulin Isotypes / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D009157:Myasthenia Gravis / Q000276:immunology* / Q000517:prevention & control*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D014101:Torpedo
D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007376:Interleukin-2; D046911:Macromolecular Substances; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins