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Circ Res. 2015 Aug 28;117(6):502-512. doi: 10.1161/CIRCRESAHA.115.306364. Epub 2015 Jul 21.

Imaging Granzyme B Activity Assesses Immune-Mediated Myocarditis.

Author information

1
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
2
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School.
3
Division of Pathology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
#
Contributed equally

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.

KEYWORDS:

dexamethasone; granzyme; immunology; molecular imaging; myocarditis

PMID:
26199323
PMCID:
PMC4553143
DOI:
10.1161/CIRCRESAHA.115.306364
[Indexed for MEDLINE]
Free PMC Article

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