title: Attenuation of experimental autoimmune myositis by blocking ICOS-ICOS ligand interaction.
abstract: Polymyositis (PM) is an acquired, systemic, connective tissue disease characterized by the proximal muscle weakness and infiltration of mononuclear cells into the affected muscles. To understand its etiology and immunopathogenesis, appropriate animal model is required. It has been demonstrated that immunization with native human skeletal C protein induces severe and reproducible experimental autoimmune myositis (EAM) in Lewis rats, and that the muscle inflammatory lesions in the EAM mimic those of human PM. In the present study, we prepared recombinant skeletal C protein fragment and succeeded in inducing as severe EAM as that by native C protein. We found ICOS expression on muscle fiber-infiltrating T cells in the EAM rats, but not in normal rats. Treatment with anti-ICOS mAb reduced incidence and severity of myositis; decreased the number of muscle-infiltrating CD11b/c+, TCR+, and CD8a+ cells; and inhibited the expression of IL-1alpha and CCL2 in the hamstring muscles of the EAM rats. However, the treatment neither inhibited serum anti-C protein IgG level, C protein-induced proliferation of lymph node (LN) cells, or LN T cells, nor production of IFN-gamma by C protein-stimulated LN cells in EAM rats. These data indicate that analysis of C protein-induced EAM provides not only insights into pathogenesis of PM, but also useful information regarding development of effective immunotherapy against the disease. ICOS-ICOS ligand interaction would be a novel therapeutic target for PM.
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Harigai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Yoh
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Kuniko
authors.initials: K
authors.lastname: Kohyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Soejima
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Masako
authors.initials: M
authors.lastname: Hara
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000502:physiology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000502:physiology / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002352:Carrier Proteins / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000096:biosynthesis; D060889:Inducible T-Cell Co-Stimulator Protein; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D017285:Polymyositis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099163:Myosin Binding Protein C