Heart transplantation is often the only available therapeutic option in end-stage heart disease. To monitor graft survival, recipients endure frequent invasive endomyocardial biopsies which carry a significant risk of complication and are prone to sampling-errors. There is thus a compelling need to develop noninvasive, more predictive and quantitative diagnostic tools to monitor individual patients and to compare new treatment regimen in different patient cohorts. An increasing body of work suggests that macrophages are highly abundant in rejected allografts, and exhibit cardinal cellular and molecular functions. The overall goal of this proposal is to evaluate macrophages and macrophage-associated functions as in vivo imaging biomarkers of transplant rejection. Specifically, we will validate a) nanoparticles as reporters of phagocytic activity, b) optical prodrugs as sensors of cysteine protease activity, and c) myeloperoxidase-targeted magnetic resonance imaging agents. We will investigate which of the above imaging marker correlates most closely with the ex vivo gold standard (ISHLT-graded histology) and CD68 expression and if imaging can detect earliest forms of rejection and/or tolerance at sufficiently high sensitivity and specificity. We will test these MU-targeted cardiac imaging tools to non-invasively investigate 3 specific therapeutic approaches to treat transplant rejection. First we will benchmark macrophage imaging during the use of routine immunosuppressants (calcineurin inhibitor, antimetabolite agent and corticosteroids). Next we will investigate emerging tolerance regimen (induction of mixed chimerism by bone marrow co- transplantation). Finally, we will use mice deficient for macrophage recruiting cytokines and adoptive cell transfer to reprogram prevalent macrophage populations in the heart from the inflammatory M1 to reparative M2 subsets. These longitudinal studies will be used to validate functional macrophage-targeted agents for noninvasive heart transplant imaging.

Public Health Relevance

Our goal is the development of molecular imaging methods to detect heart transplant rejection non-invasively. We will first investigate and then exploit the role of macrophages, increasingly appreciated to contribute to rejection, as imaging targets. The approach will be tested in several therapy trials.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Buxton, Denis B
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Massachusetts General Hospital
United States
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Swirski, Filip K; Nahrendorf, Matthias (2016) Bone Marrow Takes Center Stage in Cardiovascular Disease. Circ Res 119:701-3
Nahrendorf, Matthias; Swirski, Filip K (2016) Abandoning M1/M2 for a Network Model of Macrophage Function. Circ Res 119:414-7
Leuschner, Florian; Courties, Gabriel; Dutta, Partha et al. (2015) Silencing of CCR2 in myocarditis. Eur Heart J 36:1478-88
Nahrendorf, Matthias; Swirski, Filip K (2014) Regulating repair: regulatory T cells in myocardial infarction. Circ Res 115:7-9
Weber, Georg F; Chousterman, Benjamin G; Hilgendorf, Ingo et al. (2014) Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis. J Exp Med 211:1243-56
Pittet, Mikael J; Nahrendorf, Matthias; Swirski, Filip K (2014) The journey from stem cell to macrophage. Ann N Y Acad Sci 1319:1-18
Courties, Gabriel; Heidt, Timo; Sebas, Matthew et al. (2014) In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J Am Coll Cardiol 63:1556-66
Frantz, Stefan; Nahrendorf, Matthias (2014) Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc Res 102:240-8
Nahrendorf, Matthias; Swirski, Filip K (2014) Fluorescent leukocytes enter plaque on the microscope stage. Circ Res 114:740-1
Courties, Gabriel; Moskowitz, Michael A; Nahrendorf, Matthias (2014) The innate immune system after ischemic injury: lessons to be learned from the heart and brain. JAMA Neurol 71:233-6

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