Defining the Gut Immune Cell Landscape in anti-TNFa resistant Inflammatory Bowel Disease (IBD) Patients

Project Narrative & Hypothesis: The most effective care for IBD patients refractory to conventional medications relies on a spectrum of tumor necrosis factor alpha (TNFα) blockers, including infliximab, adalimumab, etanercept, and certolizumab pegol 1,2. However, 10-30% patients failed to demonstrate any response to initial treatment, and 23-46% patients experienced loss-of-response within 6-12 months of treatment 3. These refractory patients are collectively categorized as non-responding (NR) patients. Thus, elucidating the biological determinants that confer resistance to anti-TNFα therapy is critical for the improvement of current IBD outcomes. Polymorphonuclear neutrophils (PMNs) are the first immune cells to be recruited to sites of inflammation. These cells are professional phagocytes with primary role in bacterial killing and host defense; however, PMNs also play a prominent role in IBD pathogenesis by shaping the inflammatory environment in the colon. Indeed, anti-TNFα therapy responders (R) with infliximab (IFX, Remicade) showed reduced PMN activation (production of toxic ROS) and tissue accumulation in inflamed mucosa versus NRs (~32% of all patients), where PMNs responses were not significantly altered by the therapy 4. As such, given the emerging heterogeneity of PMNs under homeostatic and pathologic conditions, we propose that PMNs are likely contributors to the anti-TNF therapy resistance in IBD.