Jadyn James
Pronouns: She/Her
Research Mentor(s): Michael Green
Co-Presenter:
Research Mentor School/College/Department: Radiation Oncology / Medicine
Presentation Date: April 20
Presentation Type: Poster
Session: Session 2 – 11am – 11:50am
Room: League Ballroom
Authors: Jadyn James , Zhuwen Wang , Long Jiang, Ashley Pearson , Erin Holcomb, Monica Bonilla , Amanda Huber , Michael Green
Presenter: 89
Abstract
Background: Immune checkpoint inhibitors (ICI) are monoclonal antibodies used in the treatment of metastatic cancers. These treatments are highly effective, but also carry a serious and unique set of inflammatory side effects. One of the most frequent forms of toxicity is hepatitis, also known as drug induced liver injury (DILI). This is thought to be the result of an over-activation of the immune system after ICI treatment. The pathogenesis and treatment of DILI are largely unknown due to a lack of suitable animal models for investigation. Objective: This study aims to develop an appropriate murine model of DILI. Methods: Approach one: Diet-induced obesity (DIO) induces hepatic dysfunction. To understand if DIO enabled the development of ICI-hepatitis in preclinical models, C57BL/6J high fat diet (HFD) mice were treated with ICI (anti-PD1 (5mg/kg), anti-CTLA-4 (5mg/kg)) or isotype control every three days for two weeks. Wild type C57BL/6J mice were used as controls. Peripheral blood and liver tissue was collected. Serum was analyzed for AST and ALT levels and liver tissue was analyzed by histology for markers of liver damage. Approach two: Concanavalin A is a plant lectin that is used to induce autoimmune hepatitis in mice through the activation and recruitment of T cells to the liver. In this experiment, mice were intravenously injected with concanavalin a (ConA) to induce acute liver infiltration of activated T-cells driving liver inflammation. Subsequent dosing with ICI was used to drive DILI. Blood and liver were again collected and analyzed as above. Results: High fat diet in combination with ICI did not result in abnormal liver enzyme levels. The results of the serum and histology analysis from the ConA model are still in process. Conclusion: Preliminary, these data suggest that the DIO/ICI model does not enable the study of ICI induced hepatitis. Future efforts involving ConA will evaluate whether other preclinical liver injury models are more suitable. Until this work is completed, it will be challenging to gain mechanistic insight into how immunotherapy causes liver damage.
Biomedical Sciences
