The ultimate goal of the proposed research is to use non-invasive imaging methodology to improve the management of transplant patients by improving the detection and treatment of acute and chronic allograft dysfunction. The immediate objective is to use rat allograft models to develop non-invasive methods of cellular and functional magnetic resonance imaging (MRI) to monitor the infiltration of immune cells into the transplanted heart and to monitor the function of transplanted hearts, and thereby to detect early signs of allograft myocardial rejection (AMR) and cardiac allograft vasculopathy (CAV) following heart transplantation. When organ rejection occurs, immune cells accumulate at the rejecting heart. MRI contrast agents, e.g., dextran-coated ultra small superparamagnetic iron-oxide (USPIO) particles and others can be incorporated into rat macrophages and/or T-cells by phagocytosis/endocytosis. These particles or labeled cells can be introduced intravenously to monitor the accumulation of immune cells at the site of graft rejection.
The specific aims of our proposed research are: (i) to improve existing and to develop new cell labeling techniques to incorporate suitable MRI contrast agents into immune cells;(ii) to improve existing and to develop new cellular and functional MRI techniques for detecting acute and chronic cardiac rejection in vivo;(iii) to monitor by MRI the accumulation of immune cells at the rejecting heart in vivo as a new non-invasive approach to detect acute and chronic rejection and to monitor functional changes of the transplanted heart during various stages of acute and chronic rejection in vivo in our heterotopic working heart rat models with and without therapeutic intervention;and (iv) to correlate the results derived from cellular and functional MRI measurements of transplanted hearts with conventional histopathological, immunological, and biochemical parameters for evaluating cardiac rejection in order to validate our methods and to correlate infiltration of MRI-labeled immune cells with myocardial function. The proposed cardiac MRI techniques are general in nature 'and can be applied to monitor patients with other cardiac disorders, e.g., inflammatory cardiomyopathies. By allowing imaging of injured tissues at baseline and with therapeutic intervention, cellular and functional MRI offers great potential for clinical medicine. MRI tracking of cell migration can be applied to monitor the trafficking of any type of cells for research and clinical purposes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081349-04
Application #
7754078
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Evans, Frank
Project Start
2007-01-16
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$592,554
Indirect Cost
Name
Carnegie-Mellon University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Wu, Yijen L; Ye, Qing; Eytan, Danielle F et al. (2013) Magnetic resonance imaging investigation of macrophages in acute cardiac allograft rejection after heart transplantation. Circ Cardiovasc Imaging 6:965-73
Liu, Li; Hitchens, T Kevin; Ye, Qing et al. (2013) Decreased reticuloendothelial system clearance and increased blood half-life and immune cell labeling for nano- and micron-sized superparamagnetic iron-oxide particles upon pre-treatment with Intralipid. Biochim Biophys Acta 1830:3447-53
Liu, Li; Ye, Qing; Wu, Yijen et al. (2012) Tracking T-cells in vivo with a new nano-sized MRI contrast agent. Nanomedicine 8:1345-54
Mills, Parker H; Hitchens, T Kevin; Foley, Lesley M et al. (2012) Automated detection and characterization of SPIO-labeled cells and capsules using magnetic field perturbations. Magn Reson Med 67:278-89
Chen, Chih-Lung; Zhang, Haosen; Ye, Qing et al. (2011) A new nano-sized iron oxide particle with high sensitivity for cellular magnetic resonance imaging. Mol Imaging Biol 13:825-39
Wu, Yijen L; Ye, Qing; Ho, Chien (2011) Cellular and Functional Imaging of Cardiac Transplant Rejection. Curr Cardiovasc Imaging Rep 4:50-62
Hitchens, T Kevin; Ye, Qing; Eytan, Danielle F et al. (2011) 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells. Magn Reson Med 65:1144-53
Brinegar, Cornelius; Zhang, Haosen; Wu, Yi-Jen L et al. (2010) First-pass perfusion cardiac MRI using the Partially Separable Functions model with generalized support. Conf Proc IEEE Eng Med Biol Soc 2010:2833-6
Wu, Yijen L; Ye, Qing; Sato, Kazuya et al. (2009) Noninvasive evaluation of cardiac allograft rejection by cellular and functional cardiac magnetic resonance. JACC Cardiovasc Imaging 2:731-41

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