P470 Crohn’s disease patients with Ustekinumab-induced remission are characterized by high baseline p35 cytokines subunits in LPMC and high IL-23 receptor expression in the lamina propria Th1 cells

Abstract

Abstract Background Crohn’s disease (CD) is a chronic relapsing disorder of the gastrointestinal tract characterized by excessive inflammation sustained by the induction and expansion of Th1 and Th17 cells. Ustekinumab (UST), a fully humanized monoclonal antibody, is currently used for the therapy of CD patients. It acts by neutralizing both IL12 and IL23, essential for the maturation and expansion of Th1 and Th17 cells, by binding the common subunit p40. To be effective UST needs, in addition to the expression of target cytokines, the presence of cells responsive to IL12 and IL23, thus cells with IL12 and IL23 receptors. Methods This is a prospective, observational, single-center open-label study. All CD patients with clinical indications to receive UST for active luminal disease were enrolled. Patients had baseline endoscopy to confirm disease activity by SES-CD and to collect biopsies to isolate LPMC. Real-time pcr was performed to evaluate IL12 (p40 and p35) and IL23 (p40 and p19) cytokines subunits and IL12 (IL12Rb1 and IL12Rb2) and IL23 (IL12Rb1 and IL23R) receptors subunits expression in remitters (R) and not remitters (NR). Moreover, LPMCs were analyzed by flow cytometry, and IL12Rb2 and IL23R expression in Th1, Th17, and type 1 Innate lymphoid cells (iLC) cells were evaluated. Results were analyzed for clinical remission status (HBI<5) at week 16. Differences between groups were analyzed by Mann-Whitney test and statistical significance was considered for p<0.05. Results From April 2019 to November 2022, 13 CD patients were enrolled, whose clinical and demographic characteristics are enclosed in Table 1. At baseline there was no difference in IL12Rb2, ILRb1, and IL23R expression between R and NR (Fig.1). Regarding cytokines subunits, there was no difference in p19 but there was a significantly higher expression of p35 subunits in R than in NR (mean 1,52 vs 0,34; p=0,001) (Fig.1). Flow cytometry showed no difference in Th and ILCs subgroups frequency between R and NR. IL12Rb2 and IL23R were also equally expressed by Th17, Th1/Th17 and ILC1 cells in the two groups. In contrast, Th1 cells, IL23R expression was higher in R group as compared to NR (mean 20,6% vs 6,8; p=0.009) (Fig.2). Conclusion In CD patients treated with UST, higher expression p35 in LPMC and higher expression of IL23R in the lamina propria Th1 cells was associated with remission at week 16.