Document Detail


Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis.
MedLine Citation:
PMID:  17468777     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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    
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.
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MeSH Terms
Descriptor/Qualifier:
4-1BB Ligand / antagonists & inhibitors*,  immunology
Animals
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
Humans
Immunohistochemistry
Male
Matrix Metalloproteinases / metabolism
Mice
Mice, Inbred Strains
Myocarditis / drug therapy*,  pathology,  physiopathology
Myocardium / pathology,  ultrastructure
Pilot Projects
Systole / drug effects
Ventricular Remodeling / drug effects*
Grant Support
ID/Acronym/Agency:
63854-1//Canadian Institutes of Health Research; 64358-1//Canadian Institutes of Health Research; 79921-1//Canadian Institutes of Health Research
Chemical
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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