The integrin CD103 is proposed to be a potential therapeutical target in inflammatory bowel disease (IBD), as it can form a heterodimeric integrin with β7 (Etrolizumab, anti-β7 integrin) on epithelial T cells. Therefore, we aimed to study the frequencies of different intestinal CD103⁺T-cell subsets, both CD4⁺ and CD8⁺, in newly diagnosed, untreated IBD patients at baseline and during follow-up, compared with healthy controls. Intestinal biopsies from inflamed segments during colonoscopy and peripheral blood samples were prospectively taken from IBD patients at diagnosis and during follow-up. Blood and single cell suspensions from biopsies were analyzed for CD103⁺ T-cell subpopulations by flow cytometry and expressed as median percentages of the total T-cell population. In total, 75 Crohn’s disease (CD) patients, 49 ulcerative colitis (UC) patients, and 16 healthy controls were included. At presentation, IBD patients displayed lower percentages of CD103⁺T-cell subsets in inflamed biopsies: 3% (1 to 5) CD103⁺CD4⁺ in IBD vs 5% (5 to 7) in healthy controls (P = 0.007) and 9% (4 to 15) CD103⁺CD8⁺ compared with 42% (23 to 57) in healthy controls (P = 0.001). The majority of intestinal T cells was composed of CD103^-CD4⁺ T cells (65% [52 to 74]) in IBD compared with 30% (21 to 50) in healthy controls (P = 0.001). In patients with endoscopic remission during follow-up (n = 27), frequencies of CD103⁺ and CD103^-T-cell subsets were comparable with healthy controls. At diagnosis, active inflammation in IBD was associated with decreased percentages of both CD103⁺CD4⁺ and CD103⁺CD8⁺T-cell subsets in colon and ileum biopsies. In active disease during follow-up, these T-cell populations remained low but increased in remission to values comparable with healthy controls. A shift toward more CD103^-T cells was observed during active inflammation.

Immunotherapy, targeting programmed death-1 (PD-1) enhances antitumor T-cell activity in patients with malignancies. Blocking PD-1 or its ligand may lead to fulminant colitis as serious adverse eve...

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd⁺ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1⁺ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd⁺HEVs in UC at diagnosis was 4.9% (IQR 2.0%–8.3%), while none were detected in HC. During follow-up, PNAd⁺HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1⁺venules in UC at baseline was 5.8% (IQR 2.6–10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4–10.9), p = 0.001) in active disease. In conclusion, PNAd⁺HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1⁺venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.

The mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T-cell populations. Human CD4 T-cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remain incompletely understood. We performed flow cytometry, bulk, and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8αα, regulatory T cells (Tregs), CD69⁻ and CD69^high Trm T cells) in controls and Crohn’s disease (CD) patients (paired non-inflamed and inflamed). Inflammation results in alterations of the CD4 T-cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T-cell activation, increased IFNγ responses, and an effector Treg profile. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. In summary, inflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T-cell imprinting, driven by shared regulators, between the lamina propria and the epithelium. The main consequence of intraepithelial adaptation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium.

Monitoring of IBD patients on intravenous biologic treatment is recommended but time-consuming for patients and nurses. We developed a mobile application (app) to promote self-management and studied its feasibility in clinical practice. Adult IBD patients treated with intravenous infliximab or vedolizumab used the app over four biologic treatments. The app includes information modules and an interactive timeline with notifications of blood tests and health checks before treatment. In total, 55 patients participated of whom 71% had Crohn’s disease and 85% used infliximab. Compliance with health checks and blood tests was 67% before the first biologic treatment and 70, 87, and 80% before the second, third, and fourth treatment, respectively. The median number of times the app was used per treatment varied from 6 to 8 times (≥4 considered sufficient). Patients were satisfied with the app [median VAS score 8 (IQR 7–9)] and remained equally satisfied with IBD care [score 8 (IQR 8–9) before and after app use]. Nurses contacted all patients by telephone before the first biologic treatment, as previous standard care. Before the second, third, and fourth treatment only 47, 35, and 49% of patients were contacted. The majority (92%) wanted to continue using the app after the study. Monitoring of IBD patients treated with intravenous biologics using an app is feasible. We saw high compliance, sufficient app use, and high patient satisfaction. Moreover, health-care utilization was reduced and almost all patients preferred using the app over previous standard care (ClinicalTrials.gov NCT04254614).

Therapeutic strategies for patients with ulcerative colitis (UC) are based on patient- and disease-related factors in combination with drug characteristics but fail to predict success in individual patients. A considerable proportion of UC patients do not respond to the biological vedolizumab. Therefore, pretreatment biomarkers for therapeutic efficacy are urgently needed. Mucosal markers related to the integrin-dependent T lymphocyte homing could be potent predictors. We prospectively included 21 biological- and steroid-naive UC patients with moderate-to-severe disease activity planned to escalate therapy to vedolizumab. At week 0, before initiating treatment, colonic biopsy specimens were obtained for immunophenotyping and immunohistochemistry. Clinical and endoscopic disease activity were determined at week 16 after 4 infusions of vedolizumab. In addition, we retrospectively included 5 UC patients who were first treated with anti-tumor necrosis factor α before receiving vedolizumab to compare with biological-naive patients. Abundance of α4β7 on more than 8% of all CD3⁺ T lymphocytes in colonic biopsies at baseline was predictive for responsiveness to vedolizumab (sensitivity 100%, specificity 100%). The threshold for the proportion of MAdCAM-1⁺ and PNAd⁺ of all venules in the biopsies predictive for responsiveness to vedolizumab was ≥2.59% (sensitivity 89%, specificity 100%) and ≥2.41% (sensitivity 61%, specificity 50%), respectively. At week 16, a significant decrease of α4β7⁺CD3⁺T lymphocytes was demonstrated in responders (18% [12%-24%] to 8% [3%-9%]; P = .002), while no difference was seen in nonresponders (4% [3%-6%] to 3%; P = .59). UC responders to vedolizumab have a higher percentage of α4β7⁺CD3⁺ T lymphocytes and a higher proportion of MAdCAM-1⁺ venules in colonic biopsies than nonresponders before initiating therapy. Both analyses could be promising predictive biomarkers for therapeutic response and may lead to more patient tailored treatment in the future.