Imaging Granzyme B Activity Assesses Immune-Mediated Myocarditis
Rationale: The development of molecular imaging approaches that assess specific immunopathologic mechanisms can advance the study of myocarditides.
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 (FRI), validated by histologic examination. In vivo experiments localized granzyme B activity in hearts with acute myocarditis monitored by fluorescent molecular tomography in conjunction with co-registered computed tomography imaging (FMT-CT). A model anti-inflammatory intervention (dexamethasone administration) in vivo reduced granzyme B activity (vehicle vs. dexamethasone: 504±263 vs. 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.
- Cytotoxic T lymphocytes
- Anti-inflammatory agent
- molecular imaging
- immunosuppressive therapy
- myocardial inflammation
- Received March 3, 2015.
- Revision received July 17, 2015.
- Accepted July 20, 2015.