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

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-1beta, 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. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.