Positron emission tomography imaging of system xc^– in immune cells for assessment of disease activity in mice and patients with inflammatory bowel disease

Abstract

We aimed to explore whether the imaging of antiporter system xC^– of immune cells with (4S)-4-(3-[¹⁸F-fluoropropyl)-L-glutamate (¹⁸F-FSPG) positron emission tomography (PET) can assess inflammatory bowel disease (IBD) activity in murine models and patients (NCT03546868). Methods: ¹⁸F-FSPG PET imaging was performed to assess IBD activity in mice with dextran sulfate sodium-induced and adoptive T-cell transfer-induced IBD and a cohort of 20 patients at a tertiary care center in South Korea. Immunohistochemical analysis of system xC^– and cell surface markers was also studied. Results: Mice with experimental IBD showed increased intestinal ¹⁸F-FSPG uptake and xCT expression in CD11c+, F4/80+, and CD3+ cells in the lamina propria, increases positively associated with clinical and pathological disease activity. ¹⁸F-FSPG PET studies in patients, most of whom were clinically in remission or had mildly active IBD, showed that PET imaging was sufficiently accurate in diagnosing endoscopically active IBD and remission in patients and bowel segments. ¹⁸F-FSPG PET correctly identified all nine patients with superficial or deep ulcers. Quantitative intestinal ¹⁸F-FSPG uptake was strongly associated with endoscopic indices of IBD activity. The number of CD68+xCT+ and CD3+xCT+ cells in 22 bowel segments from patients with ulcerative colitis and the number of CD68+xCT+ cells in seven bowel segments from patients with Crohn’s disease showed a significant positive association with endoscopic indices of IBD activity. Conclusion: The assessment of system xC^– in immune cells may provide diagnostic information on the immune responses responsible for chronic active inflammation in IBD. ¹⁸F-FSPG PET imaging of system xC^– activity may noninvasively assess the IBD activity.