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Cardiovascular Research 2003 59(1):95-104; doi:10.1016/S0008-6363(03)00334-1
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway

Hideki Futamatsua, Jun-ichi Suzukia, Hisanori Kosugea, Osamu Yokosekib, Masafumi Kamadac, Hiroshi Itoa, Manabu Inobed, Mitsuaki Isobea,* and Toshimitsu Ueded

aDepartment of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
bThe First Department of Internal Medicine, Shinshu University School of Medicine, Nagano, Japan
cPharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Kanagawa, Japan
dDivision of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

isobemi.cvm{at}tmd.ac.jp

* Corresponding author. Tel.: +81-03-5803-5951; fax: +81-03-5803-0238.

Objective: Inducible costimulator (ICOS) is a member of the CD28 family. Although inflammation is an essential pathological feature of myocarditis, the role of ICOS in myocarditis remains unclear. Methods and Results: Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis (EAM). Flow cytometry was used to examine expression of ICOS on myocardial infiltrating cells. Anti-ICOS antibody or ICOS-immunoglobulin (ICOSIg) was administered intravenously, and rats were killed on day 14 or 21 to study effects of ICOS/ICOS-ligand (ICOSL) pathway blockade during the antigen priming phase (days 0–14) or immune response phase (days 14–21), respectively. The heart weight to body weight ratio was determined, and histological examination and echocardiogram were performed to evaluate the severity of the disease. Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed. Flow cytometry revealed that the majority of infiltrating cells, especially CD4-positive cells, expressed ICOS. Blockade of the ICOS/ICOSL pathway during the immune response phase attenuated EAM development. However, blockade of the ICOS/ICOSL pathway during the antigen priming phase did not attenuate and exacerbate EAM. Blockade of T cell activation through ICOS suppressed expression of cytokines including INF-{gamma}, IL-4, IL-6, IL-10, IL-1β, and TNF-{alpha} and inhibited T cell proliferation in vitro. Conclusions: Blockade of T cell activation through ICOS during the immune response phase regulates development of EAM, and therefore, ICOS may be an effective target for treating myocarditis.

KEYWORDS Heart failure; Immunology; Leukocytes; Lymphatic circulation; Myocarditis


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