Patients with Crohn’s Disease Achieving Ustekinumab-Induced Remission Are Characterized by Increased Baseline IL-23 Receptor Expression on Lamina Propria Th1 Cells

Background/Objectives: Ustekinumab, targeting the shared p40 subunit of interleukin (IL)-12 and IL-23, is an effective therapy for Crohn’s disease (CD), yet reliable predictors of response remain lacking. Given the central role of the IL-12/IL-23 axis in intestinal inflammation, we aimed to characterize the baseline mucosal expression of IL-12/IL-23 pathway components in lamina propria immune cells, and to explore their association with clinical response and remission following ustekinumab therapy. Methods: In this prospective, single-center study, biopsy-derived lamina propria mononuclear cells (LPMCs) were obtained from patients with CD prior to ustekinumab initiation. Gene expression of IL-12/IL-23 cytokine subunits and receptors was assessed by quantitative real-time PCR. Flow cytometry was performed to evaluate the distribution of T helper and innate lymphoid cell subsets and the expression of IL-23R and IL-12Rβ2. Clinical outcomes were assessed at week 16. Results: Fifteen consecutive patients were enrolled and included in the study. At week 16, 14/15 (93.3%) and 9/15 (60.0%) of patients reached clinical response and remission, respectively. No statistically significant differences in baseline mucosal gene expression of IL-12/IL-23 pathway components were observed between remitters and non-remitters. A trend toward higher expression of receptor subunits (IL23R, IL12RB1, IL12RB2) was observed in remitters, albeit with high variability and overlapping distributions. Similarly, cytokine subunits (IL23p19, IL12/IL23p40, IL12p35) showed no consistent differential expression pattern between the groups. In contrast, flow cytometry revealed a significantly higher frequency of IL-23R-expressing Th1 cells in remitters compared with non-remitters (20.6% vs. 6.8%, p = 0.009). Conclusions: Baseline transcriptional profiling of IL-12/IL-23 pathway components was not associated with remission following ustekinumab therapy. However, increased expression of IL-23R on mucosal Th1 cells identified a distinct immunological signature associated with clinical remission, suggesting that IL-23R expression on mucosal Th1 cells may represent a promising candidate biomarker that requires validation in larger independent cohorts.