title: Antigen-specific immunotherapeutic vaccine for experimental autoimmune myasthenia gravis.
abstract: Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused by Ab-mediated autoimmune responses to muscle nicotinic acetylcholine receptors (AChRs) that impair neuromuscular transmission, thereby causing muscle weakness. Previously, we discovered that i.p. injection of a therapeutic vaccine consisting of bacterially expressed cytoplasmic domains of human AChR subunits reduced the development of chronic EAMG in rats. In this article, we show that immunization with the therapeutic vaccine in adjuvants does not induce EAMG and, thus, is safe. The potency and efficacy of the therapeutic vaccine were greatly increased by s.c. administration of repeated low doses in IFA. Onset of chronic EAMG could be prevented. Established chronic EAMG could be rapidly reversed, modeling therapy of chronic MG. Therapy reduced pathological Abs assayed by immune precipitation of a main immunogenic region chimera. Successfully treated rats exhibited long-term resistance to reinduction of EAMG, suggesting a lasting cure of MG. A long-term effect of therapy was to change the isotype of the pathogenic Ab response from IgG2b, which fixes complement, to IgG1, which does not. Prevention and reversal of chronic EAMG was not caused by the isotype switch, but the isotype switch may contribute to resistance to reinduction of EAMG. Immunization with AChR cytoplasmic domains in adjuvant is promising as a safe, Ag-specific, potent, effective, rapidly acting, and long-lasting therapeutic approach to MG.
authors.affiliation: Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA 19104.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA 19104 jslkk@mail.med.upenn.edu.
authors.forename: Jon
authors.initials: J
authors.lastname: Lindstrom
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007074:Immunoglobulin G / Q000096:biosynthesis; D007279:Injections, Subcutaneous; D009132:Muscles / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D021122:Protein Subunits / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D014101:Torpedo; D014612:Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D014612:Vaccines