Abstract 5764: Molecular Imaging Tracking Phagocytosis and Protease Activity Reports on Cardiac Allograft Rejection
Recently developed molecular and cellular imaging techniques that probe macrophage (MΦ) functions might provide an alternative to invasive endomyocardial biopsy. Yet, which aspect of MΦ host response represents a useful marker for detecting parenchymal rejection remains uncertain. We transplanted cardiac isografts from B6 mice and allografts from Balb/c mice heterotopically into B6 recipients. During rejection, crucial Mϕ functions including phagocytosis and release of proteases render these abundant innate immune cells attractive imaging targets. Seven days after transplantation we injected either a fluorescent protease sensor or a magnetofluorescent phagocytosis sensor. Histological and flow cytometric analyses established that Mϕ function as the major cellular signal source. In vivo, we obtained a 3D functional map of Mϕ showing higher uptake of phagocytosis sensor during rejection using MRI (contrast-to-noise ratio (CNR) 51.5±8.5 in allografts (n=4) versus 19.8±8.7 in isografts (n=3), p<0.05) and higher protease activity in allografts than in isografts using fluorescence mediated tomography (FMT, fluorescence 41.2±5.2 pmol in allografts (n=8) versus 23.5±5.7 pmol in isografts (n=6), p<0.05). Finally, detection of significantly attenuated signals in recipients deficient in recombinase-1 demonstrated the sensitivity of Mϕ-targeted imaging. Reporters on either phagocytosis or protease activity can detect cardiac allograft rejection noninvasively, may facilitate the evaluation of novel tolerance-inducing strategies, and have translational potential.