EP-025 - INDUCED PLURIPOTENT STEM CELLS (IPSCS) AS A MODEL TO STUDY THIOPURINE INDUCED PANCREATITIS: PERSONALIZATION OF THERAPY IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE.

P. Rispoli¹, E. Genova², M. Lucafò², F. Yue³, M. Pelin¹, K. Sasaki³, S. Giliani⁴, M. Bramuzzo², A. Tommasini², G. Stocco¹, G. Decorti¹; ¹University of Trieste, Trieste, Italy, ²The Burlo Garofolo Pediatric Institute, Trieste, Italy, ³Shinshu University, Matsumoto, Japan, ⁴University of Brescia, Brescia, Italy.

Background: Thiopurine induced pancreatitis is a severe adverse effect that affects about 5% of the patients treated with thiopurines; its molecular mechanism is currently unknown and no clinical marker is available. This research aims to create an innovative model of the human pancreas for TIP in patients with pediatric inflammatory bowel disease (IBD).

Methods: In a case-control retrospective study, patient-derived iPSCs were generated from 5 pediatric IBD patients who developed TIP and 5 who did not develop TIP. iPSC and derived exocrine pancreatic cells were used for in vitro cytotoxicity studies, and for thiopurine metabolites measurement by LC-MS/MS analysis, after exposure to mercaptopurine and thioguanine.

Results: Cytotoxicity data show a significantly higher sensitivity of TIP-iPSCs in comparison to no-TIP-iPSCs after thioguanine exposure for 72 hours (-logEC50 [M], -6.6 ± 0.1 for no-TIP vs -6.9 ± 0.1 TIP, p=0.0002); post-hoc analysis confirmed different cell survival after exposure to 2.5x10-7 M (44 ± 8 vs 22 ± 7 % for no-TIP and TIP cells, respectively). iPSC-derived exocrine pancreatic cells show a higher sensitivity of TIP in comparison to no-TIP cells after mercaptopurine (-2.2 ± 0.8 M for no-TIP vs -2.5 ± 0.8 M for TIP patients, p = 0.011) and thioguanine exposure (-4.3 ± 0.2 M for no-TIP vs -4.8 ± 0.2 TIP patients, p = 0.014). Preliminary LC-MS/MS data indicate, after treatment for 48 hours with thioguanine 2.5x10-7 M, that thioguanosine monophosphate and its methylated form were the only identifiable metabolites. Instead, after mercaptopurine 2.5x10-7 M treatment, only thioguanosine monophosphate was detected.

Conclusion: Pancreatic iPSC-based models could help in elucidating TIP mechanism and discovering clinical biomarkers of TIP, allowing the development of personalized therapies.