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* Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan;
Departments of Pharmacovigilance and Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and
Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
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-1
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-
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported in part by grants-in-aid from the Japan Society for the Promotion of Science; the Ministry of Health, Labor, and Welfare, Japan; and the Ministry of Education, Science, Sports and Culture, Japan.
2 Address correspondence and reprint requests to Dr. Masayoshi Harigai, Department of Pharmacovigilance, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: mharigai.mpha{at}tmd.ac.jp
3 Abbreviations used in this paper: PM, polymyositis; EAM, experimental autoimmune myositis; FCM, flow cytometry; ICOSL, ICOS ligand; LN, lymph node; PLP, proteolipid protein; rh, recombinant human.
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