The goal of this proposed research project is to develop a non-invasive method to detect early signs of acute graft rejection in solid-organ transplantation, specifically by nuclear magnetic resonance (NMR) techniques, such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In order to achieve our goal, we have assembled an interdisciplinary team consisting of three interactive laboratories: (I) Chien Ho, Ph.D. of Carnegie Mellon University, a biochemist-biophysicist, and an expert in applying MRI and MRS techniques to biomedical problems; (ii) Suzanne T. lldstad, M.D. of the University of Pittsburgh, a surgeon, an immunologist, and an expert in transplantation tolerance, stem cell biology, and xenotransplantation; and (iii) Pedro J. del Nido, M.D. of Harvard Medical School and Children's Hospital of Boston, a cardiac surgeon and an expert in pediatric heart surgery, heart transplantation, and organ rejection. These three researchers have complementary expertise, have carried out collaborative research during the past three years, and have published joint scientific papers. Despite significant advances in immunosuppressive therapy for the control of graft rejection, the diagnosis of rejection remains the most difficult aspect in the management of transplant patients. Tissue biopsy is generally accepted as the """"""""gold standard"""""""" in the diagnosis of graft rejection. The use of tissue biopsies to monitor graft rejection is not only invasive, but also has other limitations and complications. Early in acute rejection, the cellular invasion process is commonly focal, affecting a discrete area of the organ. The focal nature of the early rejection process increases the likelihood of sampling error when performing a tissue biopsy. Multiple biopsies are often required, thus increasing the risk of complications, especially in pediatric patients. Our working hypothesis is that if we can develop a non-invasive method to track the movement of T-cells to the site of graft rejection, we will have a non- invasive technique to detect the early signs of organ rejection. We have chosen the rat model as our experimental system.
The specific aims of our proposed research will include the following projects: (I) to optimize the labeling of isolated T-cells with suitable MRI contrast agents, (ii) to improve the MRI detection of iron-oxide labeled T-cells; (iii) to develop MRI techniques needed for tracking T-cells labeled with various MRI contrast agents in cardiac and renal transplantations; (iv) to determine the early signs of acute rejection by comparing the MRI results (obtained from tracking T-cell movement and organ perfusion studies) with those from 31P-MRS and the conventional histological findings; and (v) to investigate immunosuppressant effects on the rat transplant model and to correlate these findings with MRI, MRS, and histological results. If our proposed approach is successful, we have high hopes of developing our methodology as a non-invasive diagnostic tool for detecting early signs of acute rejection in organ transplantation in humans. Thus, a reliable, non- invasive diagnostic technique to detect early signs of graft rejection will allow physicians more time to administer appropriate immunosuppressants therapy to prevent and to control graft rejection.
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