Hepatic allograft rejection is a significant problem following liver transplants. Up to 64% of liver transplant patients suffer from at least one episod of immune attack on the liver, which is often diagnosed through invasive liver biopsies and treated with increasing doses of immunosuppressive drugs. Liver biopsies are complicated in elderly patients due to comorbidities, and immunosuppressants have increased risks of deleterious side effects in the elderly. New methods to non-invasively monitor the immune system and the liver during hepatic allograft rejection and its treatment with immunosuppressants could be of significant benefit following liver transplants. Positron emission tomography (PET) is a non-invasive imaging technology that allows for the visualization of specific cell populations in vivo and could represent a new approach for monitoring hepatic allograft rejection. We have previously found that the PET imaging probes 18F-FDG and 18F-FAC can be used to visualize and quantify the activity of the immune system during autoimmune disease, immune-mediated tumor rejection, and following treatment with immunosuppressive drugs. Additional studies demonstrated that 18F-FDG and 18F- FAC signal represents the activity of specific and distinct immune cell populations. Finally we have preliminary evidence that the PET imaging probe 18F-DFA can be used to quantify hepatocyte function in vivo, including during immune attack of the liver. Here we propose to test preclinicall the hypothesis that PET imaging with 18F-FDG, 18F-FAC, or 18F-DFA could be leveraged for effective, non-invasive, and sensitive monitoring of immune-mediated liver rejection and facilitate titration of immunosuppressive drugs. This hypothesis will be tested through two experimental aims: (1) PET imaging with 18F-FDG, 18F-FAC, and 18F-DFA will be compared to and contrasted with traditional plasma measurements and liver histopathology in assessing immune rejection of the liver and immunosuppressive drug treatments using mouse models. (2) Cell-type specific events that account for changes in 18F-FDG, 18F-FAC, and 18F-DFA accumulation during immune-mediated liver rejection will be identified. We anticipate that the in vivo biodistribution and signal intensity of these imaging probes will be altered during different stages of immune-mediated liver rejection and following treatment with immunosuppressants. We expect that the experiments in this proposal will provide evidence that PET imaging can be used to non- invasively monitor hepatic allograft rejection and immunosuppressive drug treatments following liver transplant.
There is an unmet need for new approaches to non-invasively monitor liver rejection by the immune system following liver transplants. Such new approaches would be of great benefit to the elderly in providing alternatives to invasive liver biopsies and i enabling closer monitoring of the efficacy of immunosuppressive drugs. Here we propose to preclinically test a new imaging strategy that could be used to visualize both the immune system and the liver during immune rejection of the liver.
| Salas, Jessica R; Chen, Bao Ying; Wong, Alicia et al. (2018) 18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis. J Nucl Med 59:1616-1623 |
