Document Detail

Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis.
MedLine Citation:
PMID:  17468777     Owner:  NLM     Status:  MEDLINE    
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.
Caroline T Y Cheung; Theresa A Deisher; Honglin Luo; Bobby Yanagawa; Stefanie Bonigut; Amrit Samra; Hongyan Zhao; Elizabeth K Walker; Bruce M McManus
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-04-30
Journal Detail:
Title:  Laboratory investigation; a journal of technical methods and pathology     Volume:  87     ISSN:  0023-6837     ISO Abbreviation:  Lab. Invest.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-14     Completed Date:  2007-09-12     Revised Date:  2013-06-19    
Medline Journal Info:
Nlm Unique ID:  0376617     Medline TA:  Lab Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  651-61     Citation Subset:  IM    
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.
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MeSH Terms
4-1BB Ligand / antagonists & inhibitors*,  immunology
Antibodies, Monoclonal / immunology,  therapeutic use*
Cardiac Volume / drug effects
Cardiomyopathy, Dilated / drug therapy*,  pathology,  physiopathology
Cell Line
Coxsackievirus Infections / drug therapy*,  pathology,  physiopathology
Diastole / drug effects
Heart Ventricles / drug effects*,  pathology,  physiopathology
Matrix Metalloproteinases / metabolism
Mice, Inbred Strains
Myocarditis / drug therapy*,  pathology,  physiopathology
Myocardium / pathology,  ultrastructure
Pilot Projects
Systole / drug effects
Ventricular Remodeling / drug effects*
Grant Support
63854-1//Canadian Institutes of Health Research; 64358-1//Canadian Institutes of Health Research; 79921-1//Canadian Institutes of Health Research
Reg. No./Substance:
0/4-1BB Ligand; 0/Antibodies, Monoclonal; EC 3.4.24.-/Matrix Metalloproteinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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