Mucosal α4ß7+ Lymphocytes and MAdCAM+ Venules Predict Response to Vedolizumab in Ulcerative Colitis.

BACKGROUND: 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. METHODS: 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. RESULTS: Abundance of α4ß7 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 α4ß7+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). CONCLUSIONS: UC responders to vedolizumab have a higher percentage of α4ß7+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.

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

Therapeutic drug monitoring of thiopurines: Effect of reduced 6-thioguanine nucleotide target levels in inflammatory bowel disease patients.

AIMS: The effect of the Dutch nationwide adjustment of reducing 6-thioguanine nucleotide (6-TGN) target values (from 600-1200 to 320-630 pmol/8 × 108 red blood cells [RBC]) on toxicity and clinical outcome of thiopurine treatment in patients with inflammatory bowel disease has not yet been established. Therefore, the authors determined the incidence of toxicity-induced discontinuations and efficacy at both target concentrations. METHODS: This retrospective study was performed in inflammatory bowel disease patients treated with azathioprine or mercaptopurine. Two groups were defined: the former target (FT) group with target concentrations of 600-1200 pmol/8 × 108 RBC and the adjusted target (AT) group with target concentrations of 320-630 pmol/8 × 108 RBC. Patients were followed for maximum 52 weeks or until discontinuation of thiopurine therapy. Data were collected from the local hospital electronic health software of Rijnstate Hospital. RESULTS: In total, 151 patients were included, 76 in the FT group and 75 in the AT group. At week 52, 100 out of 151 patients (66%) of the total population discontinued thiopurine therapy. Forty-eight of the discontinuations were due toxicity (48%). The incidence of toxicity induced discontinuations was 35% in the AT group vs. 47% in the FT group (P = .25). No loss of efficacy was seen in the AT group. CONCLUSION: After reduction of the target range, there was a trend towards fewer toxicity-induced discontinuations, albeit not statistically significant. In addition, this study did not find any indication that the reduction of the target range diminished efficacy.

Homeostatic Function and Inflammatory Activation of Ileal CD8+ Tissue-Resident T Cells Is Dependent on Mucosal Location.

BACKGROUND & AIMS: Tissue-resident memory T (Trm) cells, both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease. However, data are conflicting regarding the profile of human CD8+ Trm cells, with studies suggesting both proinflammatory and regulatory functions. It is crucial to understand the functional profile of these cells in the context of (new) therapeutic strategies targeting (trafficking of) gut Trm cells. METHODS: Here, we performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103+/-CD69+CD8+ Trm cells in healthy control subjects and patients with active ileal Crohn's disease. RESULTS: Our data revealed that lamina propria CD103+CD69+CD8+ T cells have a classical Trm cell profile with active pathways for regulating cell survival/death and cytokine signaling, whereas intraepithelial CD103+CD69+CD8+ T cells display tightly regulated innate-like cytotoxic profile. Furthermore, within lamina propria CD8+CD103- Trm cells, an Itgb2+GzmK+KLRG1+ population distinct from CD103+ CD8+ Trm cells is found. During chronic inflammation, especially intraepithelial CD103+CD69+CD8+ T cells displayed an innate proinflammatory profile with concurrent loss of homeostatic functions. CONCLUSIONS: Altogether, these compartmental and inflammation-induced differences indicate that therapeutic strategies could have a different impact on the same immune cells depending on the local compartment and presence of an inflammatory milieu, and should be taken into account when investigating short- and long-term effects of new gut T cell-targeting drugs.

Distribution of mucosal PD-1 expressing T cells in patients with colitis of different etiologies.

BACKGROUND: 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 event in these patients. Since little is known of the presence and role of PD-1+T cells in colitis of different etiologies, we determined PD-1+T cells in mucosal specimens of patients with inflammatory bowel disease, infectious colitis (InfC), immunotherapy-related colitis (ImC) and healthy controls (HC). METHODS: Newly diagnosed patients with ulcerative colitis (UC, n = 73), Crohn's disease (CD, n = 50), InfC (n = 5), ImC (n = 8) and HC (n = 8) were included. Baseline inflamed colonic biopsies were studied with immunohistochemistry and flowcytometry. RESULTS: Using immunohistochemistry, PD-1 was not present on lymphocytes in the epithelium of all patients, nor in HC. The percentage PD-1+ of all lymphocytes in the lamina propria was 40% in UC, 5% in InfC, 3% in ImC and 0% in HC. Flowcytometry showed significant higher percentages of PD-1+T cells in inflamed biopsy specimens of UC patients (22%) compared to all other groups: CD patients (13%), InfC (12%), ImC (5%) and HC (6%). CONCLUSION: There are relevant differences in distribution and frequencies of mucosal PD-1+ T-cell subsets in patients with UC, CD, InfC and ImC, supporting the hypothesis that these types of colitis are driven by different immunological pathways. The increased numbers of PD-1+ and PD-L1+ lymphocytes in the colonic mucosa of UC patients suggest that the PD-1/PD-L1 pathway might be more activated in UC than in CD.

Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients.

BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs. METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index-matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared among healthy cotwins, IBD-twins, unrelated patients with IBD, and healthy controls with multivariable (ie, adjusted for potential confounding) generalized linear models. RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate <0.10). Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively (false discovery rate <0.10). Of these, 8 (42.1%) of 19 and 1 (5.6%) of 18 species, and 37 (35.2%) of 105 and 30 (19.6%) of 153 pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated patients with IBD, respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example, an increase in propionate degradation and L-arginine degradation pathways. CONCLUSIONS: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow-up studies are needed to infer a causal relationship.

Improvement of Fatigue and Quality of Life in Patients with Quiescent Inflammatory Bowel Disease Following a Personalized Exercise Program.

BACKGROUND AND AIMS: Fatigue significantly impacts the quality of life of patients with inflammatory bowel disease (IBD). This study aimed to assess the effect of a personalized, intensive exercise program on fatigue, health-related quality of life (HRQoL), and cardiorespiratory fitness in patients with quiescent IBD and severe fatigue. METHODS: A pilot study was performed including IBD patients in remission with severe fatigue. The 12-week exercise program consisted of three times per week 1-h sessions, including aerobic- and progressive-resistance training at personalized intensity based on a cardiopulmonary exercise test (CPET) and one-repetition maximum. CPET was repeated after 12 weeks. Fatigue and HRQoL were assessed using the checklist individual strength and 32-item IBD questionnaire. RESULTS: Twenty-five IBD patients with mean age of 45 (± 2.6) years were included of which 22 (88%) completed the exercise program. Fatigue significantly improved from 105 (± 17) points on the checklist individual strength before, to 66 (± 20) after completion of exercise program (p < 0.001). Patients' HRQoL significantly improved from 156 (± 21) to 176 (± 19) (p < 0.001). When looking at the subdomains of HRQoL, significant improvement was seen in emotional (58 ± 12 vs. 69 ± 9.1, p = 0.003), systemic (19 ± 3.9 vs. 24 ± 4.7, p < 0.001), and social function (25 ± 5.4 vs. 30 ± 3.9, p < 0.001). Bowel symptoms did not change (53 ± 7.7 vs. 55 ± 7.3, p = 0.208). Repeat CPET showed a significant improvement in maximum power patients were able to deliver (2.4 ± 0.5 vs. 2.7 ± 0.5 W/kg, p = 0.002). CONCLUSIONS: A personalized, intensive exercise program can lead to significant improvement of fatigue, HRQoL, and cardiorespiratory fitness in patients with quiescent IBD and severe fatigue.

Tofacitinib for ulcerative colitis: results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry.

BACKGROUND: Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). AIM: To evaluate effectiveness, safety and use of tofacitinib in daily practice. METHODS: UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. RESULTS: In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. CONCLUSION: Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.

Intestinal CD103+CD4+ and CD103+CD8+ T-Cell Subsets in the Gut of Inflammatory Bowel Disease Patients at Diagnosis and During Follow-up.

BACKGROUND: The integrin CD103 is proposed to be a potential therapeutical target in inflammatory bowel disease (IBD), as it can form a heterodimeric integrin with ß7 (Etrolizumab, anti-ß7 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Intestinal T Cell Profiling in Inflammatory Bowel Disease: Linking T Cell Subsets to Disease Activity and Disease Course.

INTRODUCTION: A dysregulated intestinal T cell response is presumed in patients with inflammatory bowel disease [IBD]. In this longitudinal study, we investigated the changes in intestinal T lymphocyte subsets in IBD at first presentation and over time during endoscopic active or inactive disease, and relate them to disease activity and outcome. METHODS: We included 129 newly diagnosed patients (87 Crohn's disease [CD], 42 ulcerative colitis [UC]) and 19 healthy controls [HC]. Follow-up biopsy specimens were analysed from 70 IBD patients. Immunophenotyping of specimens was performed by flow cytometry identifying lymphocyte subpopulations. RESULTS: IBD patients at diagnosis displayed higher percentages of CD4 T+ cells, Tregs, and central memory T cells [TCM] and with lower percentages of CD8 and CD103 T lymphocytes than HC. Follow-up specimens of patients with endoscopic inactive disease showed T cell subset recovery comparable to HC. Endoscopic active disease at follow-up coincided with T cell subsets similar to those at diagnosis. In UC, lower baseline percentages of CD3 cells was associated with milder disease course without the need of an immunomodulator, whereas in CD, higher baseline percentages of CD4 and Tregs were associated with complicated disease course. CONCLUSIONS: The intestinal T cell infiltrate in IBD patients with active endoscopic disease is composed of increased percentages of CD4+ T cells, Tregs, and TCM, with lower percentages of CD8+ T cells and CD103+ T cells, compared with HC and endoscopic inactive IBD. Baseline percentages of CD3, CD4, and Tregs were associated with disease outcome. Further research is needed to demonstrate the predictive value of these lymphocyte subsets.

The value of serum antibodies in differentiating inflammatory bowel disease, predicting disease activity and disease course in the newly diagnosed patient.

BACKGROUND: Data on serum antibodies in untreated adult inflammatory bowel disease (IBD) patients at diagnosis are scarcely available, and results on the stability of antibody presence over time are inconsistent. Our aim was to investigate antibodies in newly diagnosed, untreated IBD patients in relation to disease phenotype and course. Furthermore, we analyzed antibody presence over time. METHODS: Baseline anti-Saccharomyces cerevisiae antibodies (ASCA), anti-chitobioside carbohydrate antibodies (ACCA), anti-laminaribioside carbohydrate antibodies (ALCA) and anti-mannobioside carbohydrate antibodies (AMCA) were measured with enzyme-linked immunosorbent assays and perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA) was measured by indirect immunofluorescence in serum of 120 untreated IBD patients at diagnosis and 19 healthy controls. Antibodies were related to disease outcomes. Serial measurements were available in 71 patients. RESULTS: The combination of pANCA and ASCA enabled good discrimination between UC and CD (p = .004). Antibody presence was relatively stable over time, even though there were significant changes in concentrations. There was a trend towards larger fluctuations in concentration with immunosuppressive medication. Baseline pANCA in UC patients correlated with calprotectin values (rho = .545, p = .019) and change in pANCA status over time was associated with disease activity at that moment. No associations were found with antibodies at diagnosis and disease outcomes. CONCLUSION: Antibody profiles at diagnosis support the distinction between CD and UC. Anti-glycan antibodies are reasonably stable over time, but may fluctuate under the influence of immunosuppressive treatment which may explain the inconsistency in findings hitherto. The appearance or disappearance of pANCA antibodies during follow-up correlated with disease activity in UC and may be used in disease monitoring.

Candidate Serum Markers in Early Crohn's Disease: Predictors of Disease Course.

BACKGROUND AND AIMS: More than half of patients with Crohn's disease [CD] develop disease complications requiring aggressive medical therapy or surgery over time. However, predicting disease course and treatment response remains difficult. We therefore identified distinctive serum analytes associated with disease activity and course in newly diagnosed, untreated patients at presentation and during their follow-up. METHODS: In a pilot study, a multiplex immunoassay analysis on 36 markers was performed on serum from 20 CD patients at the time of primary diagnosis following endoscopic evaluation. The 12 most potent markers associated with disease activity, phenotype and course were analysed in a consecutive cohort of 66 CD patients at diagnosis and follow-up [n = 39]. A healthy control group [n = 20] was included as a reference. RESULTS: CD patients had higher baseline levels of sTNF-R2 [p = 0.001], sIL-2R [p = 0.0001], and MMP-1 [p = 0.001] compared with healthy controls. Serial measurements revealed that these three analytes dropped statistically significantly from baseline level during remission and were high during exacerbation. Great decline of sTNF-R1 levels was found during remission, with 6.7-fold lower levels than in healthy controls [p = 0.015]. Patients who did not respond to initial prednisone treatment had higher baseline levels of sTNF-R2 [p = 0.001]. Patients experiencing relapses during follow-up had lower baseline sTNF-R2 and VCAM levels compared with patients with long-lasting remission. CONCLUSIONS: In a large cohort of newly diagnosed untreated CD patients, we identified candidate serum markers [sTNF-R1, sTNF-R2, sIL-2R, and MMP-1] associated with disease activity. Furthermore, sTNF-R2 was associated with prednisone response and, together with VCAM, with long-lasting remission.

The Complexity of alpha E beta 7 Blockade in Inflammatory Bowel Diseases.

Monoclonal antibodies targeting integrins are emerging as new treatment option in inflammatory bowel diseases. Integrins are molecules involved in cell adhesion and signalling. After the successful introduction of anti-α4ß7, currently anti-ß7 is under evaluation in a phase three trial. Anti-ß7 blocks both α4ß7/MAdCAM-1 and αEß7/E-cadherin interaction, targeting both the homing to and the retention in the gut of potential pathological T cells. Since the physiological and potential pathological roles of immune cells expressing αEß7 are less distinct than of those expressing α4ß7, an overview of the current state of knowledge on αEß7 in mice and humans in both health and inflammatory bowel diseases is presented here, also addressing the potential consequences of anti-ß7 treatment.

Prevalence of Upper Gastrointestinal Lesions at Primary Diagnosis in Adults with Inflammatory Bowel Disease.

BACKGROUND: The prevalence of upper gastrointestinal (GI) involvement in adult inflammatory bowel disease has mostly been studied in patients with long-standing disease. The aim of this study was to prospectively evaluate the prevalence of upper GI involvement in a consecutive series of newly diagnosed, treatment-naive adult patients with inflammatory bowel disease, irrespective of upper GI tract symptoms. METHODS: Consecutive patients with suspected inflammatory bowel disease underwent combined ileocolonoscopy and upper endoscopy with biopsies. Patients diagnosed with either Crohn's disease (CD) or ulcerative colitis (UC), denying use of nonsteroidal anti-inflammatory drug, were included in the study. Helicobacter pylori infection was diagnosed histologically and positive patients were excluded from the analysis. Endoscopic and histologic lesions in the stomach and duodenum were recorded. Upper GI location (+L4) was defined as a combination of endoscopic and histological lesions. RESULTS: A total of 152 patients (108 CD and 44 UC) were analyzed. Endoscopic lesions were only seen in patients with CD (60 of 108, 55%). Histological lesions were present in both patients with CD and patients with UC: focally enhanced gastritis in 58 CD (54%) and 10 UC (23%), granulomas in 30 CD (28%). Upper GI disease location was diagnosed in 44 patients with CD (41%) and no patients with UC. Upper GI tract symptoms were reported in 14 of 44 patients (32%) with upper GI location. CONCLUSIONS: A high prevalence of upper GI involvement was observed in newly diagnosed patients with CD, with a majority of the patients being asymptomatic. Focally enhanced gastritis was common in both patients with CD and patients with UC, whereas granulomatous inflammation was restricted to patients with CD.

On naivety of T cells in inflammatory bowel disease: a review.

: Little is known about different phases of T-cell maturation in gut mucosa. Based on current knowledge about the migratory pathways of naive and memory T cells, it is believed that access to peripheral, nonlymphoid tissues is restricted to memory T cells. Surprisingly, there is increasing evidence of high numbers of naive T cells in the chronically inflamed gut tissue of patients with inflammatory bowel disease. This could partially be explained by new formation of ectopic lymphoid organs. Ongoing recruitment of naive T cells at inflammatory sites might play a role in the immunopathogenesis of inflammatory bowel disease.