title: Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Futamatsu
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kosuge
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokoseki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Manabu
authors.initials: M
authors.lastname: Inobe
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: 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*
chemical_list: D019138:Antibodies, Blocking; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D060889:Inducible T-Cell Co-Stimulator Protein