Abstract A057: The establishment of Th1 versus Th2 driven models of experimental pancreatitis

Pancreatitis is a debilitating inflammatory disease that is a precursor to pancreatic ductal adenocarcinoma (PDAC). Pancreatitis causes acute or chronic injury to acinar cells, leading to the release of trypsinogen and digestive enzymes, promoting the autodigestion of the pancreas. Despite the high risk of PDAC development, there are no mechanism-based therapies for treating pancreatitis, with patients generally receiving palliative care. Further, immune checkpoint inhibitor-induced pancreatitis (ICI-P) has presented clinical challenges from anti-PD-1, anti-PD-L1, and anti-CTLA-4 use in cancer treatment. We found that pancreatic acinar cells express cytokine receptors that can directly respond to inflammatory cues in vitro and in vivo. We have developed an immune-mediated model of pancreatitis using the stable mimic of IL-21 (21h10). Daily treatment of 21h10 leads to progressive acinar cell loss, progressing to lethal pancreatitis after 3-4 weeks of treatment as detected by serum amylase levels and pancreatic histology. We compared caerulein-mediated acute pancreatitis to 21h10 chronic pancreatitis by single cell transcriptional profiling, confirming a distinct difference in CD4 T cell polarization. Mice lacking eosinophils are partially protected from caerulein-mediated but not 21h10-mediated pancreatitis, whereas the reverse is true for mice genetically lacking TNFa. We suggest that caerulein-induced (acute, recurrent) pancreatitis is driven by Th1 responses (IL-4 and IL-13) and 21h10 (immune-mediated, autoimmune) pancreatitis is driven by Th1 responses (IL-21, TNFa, IFNg). Thus, we hypothesize that acinar cells may be evolutionary adapted to respond to Th1 cytokines by apoptotic cell death and to Th2 cytokines by rapid acinar to ductal metaplasia (ADM). Citation Format: Corey M. Perkins, Katherine J. Aney, Megan T. Hoffman, Tavus Atajanova, Frank Peprah, Julissa G. Tello, David Baker, Michael Dougan, Sahar Nissim, Stephanie K. Dougan. The establishment of Th1 versus Th2 driven models of experimental pancreatitis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A057.