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.


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-1 beta, 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.
Futamatsu
Hideki
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Suzuki
Jun-ichi
J
Kosuge
Hisanori
H
Yokoseki
Osamu
O
Kamada
Masafumi
M
Ito
Hiroshi
H
Inobe
Manabu
M
Isobe
Mitsuaki
M
Uede
Toshimitsu
T
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D004452:Echocardiography; D005434:Flow Cytometry; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation; D008297:Male; D009205:Myocarditis / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*
D019138:Antibodies, Blocking; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D060889:Inducible T-Cell Co-Stimulator Protein