title: Adenovirus-mediated ICOSIg gene transfer alleviates cardiac remodeling in experimental autoimmune myocarditis.
abstract: To explore the therapeutic effects of adenovirus vector mediated transfer of the ICOSIg gene on immuno-inflammation-mediated cardiac remodeling in an experimental autoimmune myocarditis (EAM) model, pAdeno-ICOSIg was constructed and transfected into HEK 293 cells to produce the ICOSIg adenovirus. Ad-CMV-GFP was used as a control. EAM was induced in Lewis rats by injection of porcine cardiac myosin. The immunized rats were divided into two groups. The inducible co-stimulatory molecule (ICOS) group received the adenovirus containing ICOSIg on day 14; the green fluorescent protein (GFP) group received the adenovirus containing GFP as the control adenovirus and 15 normal rats (Control group) consisted of the normal controls that were not immunized. On day 28, all rats were euthanized after echocardiography and histopathologically examined for cardiac fibrosis. Western blotting was performed to detect ICOS, ICOS ligand (ICOSL), matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 and real-time RT-PCR was performed to detect B7-1, B7-2 and interleukin (IL)-17 expression. ELISPOT was applied to detect Th1 and Th2 cytokine production. Collagen concentration and collagen cross-linking were determined as markers of cardiac fibrosis. It was found that blockade with ICOSIg exerted antifibrotic effects on cardiac remodeling in EAM. On day 28, cardiac function and inflammatory myocardial fibrosis improved significantly in the ICOS group compared to the GFP group. The expression of ICOS, the ICOSL, B7-1 and IL-17 was statistically significantly lower in the ICOS and Control groups compared to the GFP group. ICOSIg significantly augmented Th2 cytokine production and diminished Th1 and Th17 cytokine production. This blockade of the ICOS co-stimulatory pathway with ICOSIg alleviated autoimmune inflammation-mediated cardiac remodeling and improved cardiac function. Regulation of the Th1/Th2/Th17 balance may be one of the underlying mechanisms responsible for this effect.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Harbin Medical University, Heilongjiang, China. doctor_liuwei@yahoo.com.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Weiwei
authors.initials: W
authors.lastname: Feng
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Baoguo
authors.initials: B
authors.lastname: Zhou
authors.forename: Cheng
authors.initials: C
authors.lastname: Gao
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Yihui
authors.initials: Y
authors.lastname: Kong
authors.forename: Manling
authors.initials: M
authors.lastname: Ma
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D003094:Collagen / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006334:Heart Function Tests; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009218:Myosins