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From bench to patient and back - an interdisciplinary mixed-method patient-integrated approach to developing a new potential therapy for inflammatory bowel disease

University of British Columbia

Inflammatory Bowel Disease (IBD) is life-changing because of recurrent intestinal inflammation. Current therapies are associated with mild to severe side effects, and none provide a cure. Recent research has provided pre-clinical and clinical data on cell-based therapy using the two best-characterized types of T regulatory cells, Foxp3⁺ Tregs and Foxp3⁻ Type 1 regulatory (Tr1) cells. However, major hurdles exist. The ability of Tregs to regulate innate immunity is not well understood, and while high numbers of antigen-specific Tregs are needed, these cells are scarce. Studies showed that engineered chimeric antigen receptor-expressing Tregs (CAR-Treg) could curb intestinal inflammation, but these CARs were not relevant to human disease. CAR-Treg therapy is logistically and conceptually complex and patients might perceive an unacceptable risk to be associated with this therapy. Finally, people living with IBD have an increased risk of Clostridioides difficile infection (CDI), the most prevalent cause of nosocomial infectious diarrhea in Canada, and patient experiences with CDI have not been researched. The purpose of this thesis was to elucidate how Tr1 cells and/or Tregs regulate innate immunity, which I addressed by investigating the suppressive effect of Tr1 and Tregs on the inflammasome. I then developed and tested a new CAR-Treg relevant to human IBD and conducted a survey to investigate patients’ willingness to try CAR-Treg. Finally, I analyzed a survey to describe the impact of CDI on patients in Canada. My results demonstrate that Tr1 cells may have unique therapeutic effects in reducing inflammasome activation via Interleukin 10. I provide evidence that CAR-Tregs suppress proinflammatory T cells. People with IBD indicated high willingness to try CAR-Treg therapy in both a clinical trial and as a new treatment. Willingness to try was not correlated with disease state or medication history. Finally, CDI patients highlighted the symptom-related impact and long-lasting effect on quality of life. Patient priorities to attenuate impact include reducing time to diagnosis and improving patient education. My research has implications on future development of Treg-based therapy for IBD and other immune-mediated diseases and demonstrates the promise of moving this therapy into clinical practice, as most patients indicated willingness to try.

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2020-12-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76916

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/