title: Imaging Granzyme B Activity Assesses Immune-Mediated Myocarditis.
abstract: BACKGROUND
  The development of molecular imaging approaches that assess specific immunopathologic mechanisms can advance the study of myocarditis.
  
  
  OBJECTIVE
  This study validates a novel molecular imaging tool that enables the in vivo visualization of granzyme B activity, a major effector of cytotoxic CD8+ T lymphocytes.
  
  
  RESULTS
  We synthesized and optimized a fluorogenic substrate capable of reporting on granzyme B activity and examined its specificity ex vivo in mice hearts with experimental cytotoxic CD8+ T lymphocyte-mediated myocarditis using fluorescence reflectance imaging, validated by histological examination. In vivo experiments localized granzyme B activity in hearts with acute myocarditis monitored by fluorescent molecular tomography in conjunction with coregistered computed tomography imaging. A model anti-inflammatory intervention (dexamethasone administration) in vivo reduced granzyme B activity (vehicle versus dexamethasone: 504±263 versus 194±77 fluorescence intensities in hearts; P=0.002).
  
  
  CONCLUSIONS
  Molecular imaging of granzyme B activity can visualize T cell-mediated myocardial injury and monitor the response to an anti-inflammatory intervention.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
authors.forename: Masanori
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School.
authors.forename: S Sibel
authors.initials: SS
authors.lastname: Erdem
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Division of Pathology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School.
authors.forename: Jason R
authors.initials: JR
authors.lastname: McCarthy
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D004789:Enzyme Activation / Q000502:physiology; D005456:Fluorescent Dyes / Q000032:analysis; D053804:Granzymes / Q000032:analysis / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009205:Myocarditis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology
chemical_list: D005456:Fluorescent Dyes; D053804:Granzymes; C509214:Gzmb protein, mouse
keywords: dexamethasone; granzyme; immunology; molecular imaging; myocarditis