title: Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis.
abstract: Coxsackievirus B3 (CVB3) is the most common causative agent of infectious myocarditis. Chronic inflammation, loss of contractile tissue, and maladaptive remodeling all contribute to dilated cardiomyopathy and heart failure. The 4-1BB receptor is a costimulatory molecule expressed by T cells and cardiomyocytes. We infected mice with CVB3 to examine if virus infection triggers 4-1BB activation and whether inhibition of this pathway will reduce inflammation and improve heart function. Echocardiography was performed on days 3, 9, 30 and at 10 weeks post-infection (pi) and ejection fraction (EF), left ventricular (LV) wall thickness, contractility, and internal cardiac dimensions were measured. At day 9, reduced rate of wall thickening (30+/-17 vs 70+/-19%), increased LV wall thickness (0.15+/-0.04 vs 0.09+/-0.01 cm in diastole and 0.19+/-0.04 vs 0.15+/-0.02 cm in systole), and reduced cardiac volume (0.013+/-0.004 vs 0.023+/-0.003 ml in diastole and 0.004+/-0.002 ml vs 0.007+/-0.001 ml in systole) were observed in infected hearts as compared with shams. At 14 days pi, CVB3-infected mice were randomly assigned to receive either anti-4-1BBL neutralizing (M522) or control antibodies (Ab) for 8 weeks. Cardiac damage, fibrosis, and inflammation were assessed by histological stains and immunohistochemistry. Polymerase chain reaction (PCR) was utilized to detect matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12 expressions. At 10 weeks pi, M522 treatment improved LV wall thickening rate (-10+/-13 vs -49+/-16%, expressed as percentage change from baseline) and reduced diastolic LV posterior wall thickness (17+/-10 vs 57+/-47%, expressed as percentage change from baseline), cardiac damage as assessed by histological scores (0 vs 1.3+/-1.5), fibrosis by collagen volume fraction (3.2+/-0.6 vs 4.9+/-2.2%), overall inflammation (5.9+/-1.3 vs 8.5+/-4.1%), and T-cell infiltration (1.3+/-0.9 vs 4.3+/-3.8%) as compared to control. MMP-12 was highly increased during acute and chronic myocarditis, but was significantly decreased by M522 treatment. Thus, long-term inhibition of the 4-1BB pathway reduces cardiac damage, remodeling, and inflammation during viral myocarditis.
authors.affiliation: Department of Pathology and Laboratory Medicine, The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St Paul's Hospital/Providence Health Care, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Caroline T Y
authors.initials: CT
authors.lastname: Cheung
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Deisher
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.forename: Bobby
authors.initials: B
authors.lastname: Yanagawa
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bonigut
authors.forename: Amrit
authors.initials: A
authors.lastname: Samra
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Walker
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
mesh_terms: D053330:4-1BB Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002306:Cardiac Volume / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009205:Myocarditis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D010865:Pilot Projects; D013599:Systole / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D020782:Matrix Metalloproteinases