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(Circulation. 2009;119:1925-1932.)
© 2009 American Heart Association, Inc.

Imaging

Molecular Imaging of Innate Immune Cell Function in Transplant Rejection

Thomas Christen, MD, PhD^*; Matthias Nahrendorf, MD, PhD^*; Moritz Wildgruber, MD; Filip K. Swirski, PhD; Elena Aikawa, MD, PhD; Peter Waterman, BS; Koichi Shimizu, MD, PhD; Ralph Weissleder, MD, PhD; Peter Libby, MD

From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston (T.C., K.S., P.L.); Center for Systems Biology, Massachusetts General Hospital, Boston (M.N., F.S., P.W., R.W.); Department of Systems Biology, Harvard Medical School, Boston (R.W.); and Center for Molecular Imaging Research, Massachusetts General Hospital, and Harvard Medical School, Charlestown (M.N., E.A., M.W., F.K.S., P.W., Y.I., R.W.), Mass.

Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, NRB 741, 77 Ave Louis Pasteur, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Received June 4, 2008; accepted January 30, 2009.

Background— Clinical detection of transplant rejection by repeated endomyocardial biopsy requires catheterization and entails risks. Recently developed molecular and cellular imaging techniques that visualize macrophage host responses could provide a noninvasive alternative. Yet, which macrophage functions may provide useful markers for detecting parenchymal rejection remains uncertain.

Methods and Results— We transplanted isografts from B6 mice and allografts from Balb/c mice heterotopically into B6 recipients. In this allograft across major histocompatability barriers, the transplanted heart undergoes predictable progressive rejection, leading to graft failure after 1 week. During rejection, crucial macrophage functions, including phagocytosis and release of proteases, render these abundant innate immune cells attractive imaging targets. Two or 6 days after transplantation, we injected either a fluorescent protease sensor or a magnetofluorescent phagocytosis marker. Histological and flow cytometric analyses established that macrophages function as the major cellular signal source. In vivo, we obtained a 3-dimensional functional map of macrophages showing higher phagocytic uptake of magnetofluorescent nanoparticles during rejection using magnetic resonance imaging and higher protease activity in allografts than in isografts using tomographic fluorescence. We further assessed the sensitivity of imaging to detect the degree of rejection. In vivo imaging of macrophage response correlated closely with gradually increasing allograft rejection and attenuated rejection in recipients with a genetically impaired immune response resulting from a deficiency in recombinase-1 (RAG-1^–/–).

Conclusions— Molecular imaging reporters of either phagocytosis or protease activity can detect cardiac allograft rejection noninvasively, promise to enhance the search for novel tolerance-inducing strategies, and have translational potential.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 119: 1843-1845. [Extract] [Full Text]