F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis.

Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (F-FDG and F-1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine [F-FAC]) and hepatocyte biology (F-2-deoxy-2-fluoroarabinose [F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged with F-FDG, F-FAC, and F-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with F-FDG, F-FAC, and F-DFA PET. F-FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Hepatic accumulation of F-FDG and F-FAC was 173% and 61% higher, respectively, and hepatic accumulation of F-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepatic F-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepatic F-FDG accumulation by 109% and decreased hepatic F-DFA accumulation by 20% but had no effect on hepatic F-FAC accumulation (nonsignificant 2% decrease). F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation of F-FAC. Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis.