Imaging Granzyme B activity assesses immune-mediated myocarditis


Konishi M., Erdem S. S., Weissleder R., Lichtman A. H., Mccarthy J. R., Libby P.

Circulation Research, vol.117, no.6, pp.502-512, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 117 Issue: 6
  • Publication Date: 2015
  • Doi Number: 10.1161/circresaha.115.306364
  • Journal Name: Circulation Research
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.502-512
  • Keywords: dexamethasone, granzyme, immunology, molecular imaging, myocarditis
  • Istanbul Medipol University Affiliated: No

Abstract

Rationale: 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. Methods and 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.