DEVELOPMENT OF MRI TO DETECT CARDIAC REJECTION

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DESCRIPTION (provided by applicant): 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.