Magnetic resonance imaging investigation of macrophages in acute cardiac allograft rejection after heart transplantation.
Date of Original Version
Abstract or Description
BACKGROUND: Current immunosuppressive therapy after heart transplantation either generally suppresses the recipient's entire immune system or is mainly targeting T-lymphocytes. Monocytes/macrophages are recognized as a hallmark of acute allograft rejection, but the roles that they play are not well characterized in vivo, because the tools for accessing in situ macrophage infiltration are lacking. In this study, we used MRI to investigate the role of macrophages in acute heart allograft rejection by cellular and functional MRI with selectively depleted systemic macrophages without affecting other leukocyte population, as well as to explore the possibility that macrophages could be an alternative therapeutic target.
METHODS AND RESULTS: A rodent heterotopic working heart-lung transplantation model was used for studying acute allograft rejection. Systemic macrophages were selectively depleted by treating recipient animals with clodronate-liposomes. Macrophage infiltration in the graft hearts was monitored by cellular MRI with in vivo ultrasmall superparamagnetic iron oxide particles labeling. Graft heart function was evaluated by tagging MRI followed by strain analysis. Clodronate-liposome treatment depletes circulating monocytes/macrophages in transplant recipients, and both cellular MRI and pathological examinations indicate a significant reduction in macrophage accumulation in the rejecting allograft hearts. In clodronate-liposome-treated group, allograft hearts exhibited preserved tissue integrity, partially reversed functional deterioration, and prolonged graft survival, compared with untreated controls.
CONCLUSIONS: Cardiac cellular and functional MRI is a powerful tool to explore the roles of targeted immune cells in vivo. Our results indicate that macrophages are essential in acute cardiac allograft rejection, and selective depletion of macrophages with clodronate-liposomes protects hearts against allograft rejection, suggesting a potential therapeutic avenue. Our findings show that there is a finite risk of forming an intraventricular mass, presumably from the cellular debris or lipid material. Further optimization of the dosing protocol is necessary before clinical applications.
Circulation: Cardiovascular Imaging, 6, 6, 965-973.