Safety and efficacy of salvage endoscopic submucosal dissection for Barrett's neoplasia recurrence after radiofrequency ablation.

BACKGROUND AND STUDY AIMS: This study evaluated the safety and efficacy of salvage endoscopic submucosal dissection for Barrett's neoplasia recurrence after radiofrequency ablation. PATIENTS AND METHODS: Data from patients at sixteen centers were collected for a multicentric retrospective study. Patients who underwent at least one RFA treatment for Barrett's esophagus and thereafter underwent further esophageal ESD for neoplasia recurrence were included. RESULTS: Data from 56 patients treated by salvage ESD performed between April 2014 and November 2022 were collected. Immediate complications included one muscular tear (1.8%) treated with stent (Agree classification: grade IIIa), two patients had transmural perforations (4%) and five patients had muscular tears (9%) treated with clips and without clinical impact and not considered as adverse event. Seven patients (12.5%) developed strictures, treated by balloon dilation (grade IIIa). Histological analysis showed 36 adenocarcinomas, 17 high-grade dysplasia, and 3 low-grade dysplasia. En-bloc and R0 resection rates were 89% and 66%, respectively. Resections were curative in thirty-three patients (59%), non-curative in 22 patients (39%), including 11 "local risk" (19.5%) and 11 "high risk" resections (19.5%). At the end of follow-up with a median time of 14 [0-75] months after salvage ESD eventually associated with further endoscopic treatment (RFA, argon plasma coagulation, endoscopic mucosal resection, ESD), neoplasia remission ratio was 37/53 (70%) and the median remission time was 13 [1-75] months. CONCLUSION: In expert hands, salvage ESD is a safe and effective treatment for recurrence of Barrett's neoplasia after RFA treatment.

Outcome of Biological Therapies and Small Molecules in Ulcerative Proctitis: A Belgian Multicenter Cohort Study.

BACKGROUND & AIMS: Several advanced therapies (biologic therapies and small molecules) have been approved for the treatment of moderate-to-severe ulcerative colitis. The registration trials for these agents typically excluded patients with isolated proctitis, leaving an evidence gap. We evaluated efficacy and safety of advanced therapies in patients with ulcerative proctitis (UP). METHODS: This multicenter retrospective cohort study included consecutive patients with active UP (Mayo endoscopy subscore of ≥2, rectal inflammation up to 15 cm) initiating advanced therapy, after failing conventional therapy. The primary end point was short-term steroid-free clinical remission (total Mayo score ≤2 with no individual subscore >1). In addition, drug persistence and relapse-free and colectomy-free survival were assessed. Both binary logistic and Cox regression analyses were performed. RESULTS: In total, 167 consecutive patients (52.0% female; median age 41.0 years; 82.0% bionaive) underwent 223 courses of therapy for UP (38 adalimumab, 14 golimumab, 54 infliximab, 9 ustekinumab, 99 vedolizumab, 9 tofacitinib). The primary end point was achieved with 36.3% of the treatment courses, and based on multivariate analysis, more commonly attained in bionaive patients (P = .001), patients treated with vedolizumab (P = .001), patients with moderate endoscopic disease activity (P = .002), and a body mass index <25 kg/m2 (P = .018). Drug persistence was significantly higher in patients treated with vedolizumab (P < .001) and patients with a shorter disease duration (P = .006). No new safety signals were observed. CONCLUSIONS: Advanced therapies are also efficacious and safe in patients with ulcerative colitis limited to the rectum. Therefore, the inclusion of patients with UP in future randomized-controlled trials should be considered.

Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).

Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases.

BACKGROUND: The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction. METHODS: This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30. RESULTS: Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ±â€…0.12, a sensitivity of 89%, and a specificity of 75%. CONCLUSIONS: This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management.

A plethora of manifestations following a Mycoplasma pneumoniae infection: a case report.

Mycoplasma pneumoniae infection can present with a plethora of symptoms and result in a systemic vasculitis by activating a cascade of autoimmune reactions. In this case report, a young man without relevant past medical history was admitted to the hospital with diarrhea, abdominal pain and spiking fever. A CT-scan showed terminal ileitis. A 5-day broad spectrum antibiotic treatment (ciprofloxacin/clindamycin) did not result in any clinical improvement. On the contrary, the patient developed a cholestatic hepatitis, bilateral anterior uveitis and a dry cough. Extensive serological testing finally led to the diagnosis of a M. pneumoniae infection by paired serology (≥4-fold rise in IgG titer). In the diagnostic work-up, a PET-CT was performed and showed increased tracer uptake in the carotids and vertebral arteries, suggesting the diagnosis of vasculitis. After start of azithromycin and low-dose corticosteroids (0.5 mg/kg/day), a gradual clinical and biochemical improvement was observed. But subsequently, the patients relapsed and presented with an acute coronary syndrome. Coronary angiography revealed aneurysmatic deformation of the three coronary arteries, leading to the assumption of coronary vasculitis. Clinical improvement was achieved with high-dose corticosteroids (1 mg/kg/day). This case shows that M. pneumoniae is not merely a pulmonary infection, but that its primary symptoms can be diverse and misleading. All clinicians should be aware of its extrapulmonary manifestations.

Curriculum for endoscopic submucosal dissection training in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

There is a need for well-organized comprehensive strategies to achieve good training in ESD. In this context, the European Society of Gastrointestinal Endoscopy (ESGE) have developed a European core curriculum for ESD practice across Europe with the aim of high quality ESD training.Advanced endoscopy diagnostic practice is advised before initiating ESD training. Proficiency in endoscopic mucosal resection (EMR) and adverse event management is recommended before starting ESD trainingESGE discourages the starting of initial ESD training in humans. Practice on animal and/or ex vivo models is useful to gain the basic ESD skills. ESGE recommends performing at least 20 ESD procedures in these models before human practice, with the goal of at least eight en bloc complete resections in the last 10 training cases, with no perforation. ESGE recommends observation of experts performing ESD in tertiary referral centers. Performance of ESD in humans should start on carefully selected lesions, ideally small ( < 30 mm), located in the antrum or in the rectum for the first 20 procedures. Beginning human practice in the colon is not recommended. ESGE recommends that at least the first 10 human ESD procedures should be done under the supervision of an ESD-proficient endoscopist.Endoscopists performing ESD should be able to correctly estimate the probability of performing a curative resection based on the characteristics of the lesion and should know the benefit/risk relationship of ESD when compared with other therapeutic alternatives. Endoscopists performing ESD should know how to interpret the histopathology findings of the ESD specimen, namely the criteria for low risk resection ("curative"), local risk resection, and high risk resection ("non-curative"), as well as their implications. ESD should be performed only in a setting where early and delayed complications can be managed adequately, namely with the possibility of admitting patients to a ward, and access to appropriate emergency surgical teams for the organ being treated with ESD.

Incidence and Predictors of Success of Adalimumab Dose Escalation and De-escalation in Ulcerative Colitis: a Real-World Belgian Cohort Study.

Background: Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%-25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM. Methods: We included 231 consecutive patients from 10 Belgian centers initiating ADM treatment for active UC before September 1, 2015 (follow-up ≥1 year in each patient). We performed detailed chart review to identify variables associated with short-term clinical benefit (based on physician global assessment and absence of rectal bleeding at week 10), success of dose escalation, and dose de-escalation. Backward Cox regression and Wald Logistic regression were used to identify predictive variables. Results: Short-term clinical benefit was achieved in 101 patients (44%) and was less frequent in infliximab failures [37% vs 50%, Odds ratio 0.57 (95% CI 0.34-0.97), P = 0.038]. After a median of 2.8 (1.7-5.1) months, 164 patients (71%) needed ADM discontinuation (n = 35, 15%) or dose escalation (n = 129, 56%). Dose escalation was successful in 77/129 (60%). Dose de-escalation was attempted in 71% (55/77) after a median of 4.3 (2.9-7.2) months and was successful in 80% (43/54). Conclusions: In this cohort, 56% of patients with UC required ADM dose escalation with a 60% success rate. Of note, most patients could be successfully de-escalated later on.

Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned.

LESSONS LEARNED: Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible. BACKGROUND: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. METHODS: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. RESULTS: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. CONCLUSION: Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. METHODS: We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case-control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. RESULTS: We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohn's disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. CONCLUSIONS: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use.

Small-bowel Surveillance in Patients With Peutz-Jeghers Syndrome: Comparing Magnetic Resonance Enteroclysis and Double Balloon Enteroscopy.

BACKGROUND AND STUDY AIMS: Small-bowel surveillance with polypectomy of polyps ≥15 mm prevents complications in patients with Peutz-Jeghers syndrome (PJS). We aimed to compare magnetic resonance enteroclysis (MRE) and double balloon enteroscopy (DBE) for diagnostic yield of these polyps and for patient preference. MATERIALS AND METHODS: PJS patients prospectively underwent MRE followed by proximal DBE within 20 weeks. Endoscopists were blinded to the MRE results. We compared number of polyps ≥15 mm detected by MRE and DBE. Patients' perceptions of both procedures were assessed using questionnaires. RESULTS: Fifteen PJS patients (67% males, median age 47 y) underwent both MRE and DBE. Polyps ≥15 mm were identified by MRE and/or DBE in 12/15 (80%) patients. There was no significant difference in the detection of polyps ≥15 mm (38 by MRE vs. 50 by DBE, P=0.37). Sensitivity for these polyps was 62% (38/61) for MRE and 82% (50/61) for DBE. Patients' perceived shame and burden did not differ significantly between MRE and DBE. Patients reported significantly more pain during preparation for MRE than for DBE (moderate vs. no pain, P=0.02), although perceived pain during the procedures was comparable (both mild, P=0.89). For future small-bowel surveillance 10/13 (77%) patients preferred DBE over MRE (P=0.09). CONCLUSIONS: Our results suggest that MRE and DBE have a comparable diagnostic yield of polyps ≥15 mm. However, DBE allows for direct intervention and was preferred over MRE by most patients in this series. Larger cohorts of PJS patients are needed to fully evaluate the diagnostic yield of DBE compared with other modalities.

Use of visible light spectroscopy to diagnose chronic gastrointestinal ischemia and predict response to treatment.

BACKGROUND & AIMS: Chronic gastrointestinal ischemia (CGI) is more common than previously thought. Visible light spectroscopy (VLS) allows for noninvasive measurements of mucosal capillary hemoglobin oxygen saturation during endoscopy. We evaluated the response of patients with occlusive CGI to treatment after evaluation by radiologic imaging of the vasculature and VLS. We also identified factors associated with response to treatment in these patients. METHODS: In a prospective study, we collected data from 212 patients referred for evaluation of suspected CGI from November 2008 through January 2011. Patients underwent an extensive evaluation that included visualization of gastrointestinal arteries and assessments of mucosal perfusion by means of VLS. Treatment response was evaluated in patients with occlusive CGI. Factors associated with response to therapy were assessed by using multivariate logistic regression analysis. RESULTS: Occlusive CGI was diagnosed in 107 patients (50%); 96 were offered treatment (90%). After median follow-up period of 13 months, data on treatment response were available from 89 patients (93%); 62 patients had a sustained response (70%). Weight loss before treatment (odds ratio [OR], 1.93), presence of an abdominal bruit (OR, 2.36), and corpus mucosal saturation level <56% (OR, 4.84) were the strongest predictors of a positive response to treatment. CONCLUSIONS: Treatment of CGI, diagnosed by a multimodal approach, provides a substantial long-term rate of response (70% in 13 months). Weight loss, abdominal bruit, and low corpus mucosal saturation identify patients most likely to respond to treatment. Multiple techniques should therefore be used to assess patients with CGI, including VLS measurements, to detect mucosal hypoxia.

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI).

OBJECTIVE: To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn's disease (CD). DESIGN: Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohn's Disease Activity Index, Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed. CONCLUSIONS: Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00736983.

[Treatment of patients with severe glucocorticoid-refractory ulcerative colitis: cyclosporine or infliximab?]. / Behandeling van patiënten met ernstige glucocorticoïd-refractaire colitis ulcerosa: ciclosporine of infliximab?

Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis. A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe ulcerative colitis. Cyclosporine may be prescribed as a bridge to treatment with thiopurines; infliximab may be prescribed when a patient is intolerant or refractory to thiopurines. Preoperative treatment with cyclosporine or infliximab does not affect the number of postoperative complications.

Small bowel endoscopy and Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disease. It is clinically characterized by the development of gastrointestinal hamartomas, mainly located in the small bowel. These hamartomas are prone to complications such as intussusceptions, abdominal complaints and anaemia. Furthermore, patients are at increased risk for developing small bowel cancer. Therefore, regular surveillance of the small bowel is indicated. However, the optimal strategy for surveillance has not been determined yet. This review gives an overview of the different techniques that have been described to examine the small bowel of PJS patients. First, a number of radiologic and endoscopic imaging modalities with diagnostic value are discussed. Secondly, recently developed advanced endoscopy techniques are described that can serve both as a diagnostic and therapeutic tool in the surveillance of the small bowel. Finally, a recommendation is given how to apply these individual techniques for small bowel surveillance in a step-up approach.

Cutting edge: the chemokine receptor CXCR3 retains invariant NK T cells in the thymus.

The current model used to define T cell export from the thymus suggests that emigrating lymphocytes seed the peripheral organs as functionally mature cells. This model holds true for the majority of T cells exported from the thymus with the exception of invariant NK T (iNKT) cells. iNKT cells undergo lineage expansion after positive selection and acquire NK receptor expression once fully mature; yet, the majority of mature iNKT cells are retained in the thymus by an as of yet unidentified mechanism. In this study we demonstrate that mature iNKT cells are retained in the thymus by the chemokine receptor CXCR3. We propose that the expression of CXCR3 ligands in the thymic medullary epithelium promotes the chemotactic retention of mature iNKT thymocytes and prevents leakage of iNKT cells into the peripheral circulation.

LTbetaR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen.

The formation of lymph nodes is a complex process crucially controlled through triggering of LTbetaR on mesenchymal cells by LTalpha(1)beta(2) expressing lymphoid tissue inducer (LTi) cells. This leads to the induction of chemokines to attract more hematopoietic cells and adhesion molecules to retain them. In this study, we show that the extravasation of the first hematopoietic cells at future lymph node locations occurs independently of LTalpha and that these cells, expressing TNF-related activation-induced cytokine (TRANCE), are the earliest LTi cells. By paracrine signaling the first expression of LTalpha(1)beta(2) is induced. Subsequent LTbetaR triggering on mesenchymal cells leads to their differentiation to stromal organizers, which now also start to express TRANCE, IL-7, as well as VEGF-C, in addition to the induced adhesion molecules and chemokines. Both TRANCE and IL-7 will further induce the expression of LTalpha(1)beta(2) on newly arrived immature LTi cells, resulting in more LTbetaR triggering, generating a positive feedback loop. Thus, LTbetaR triggering by LTi cells during lymph node development creates a local environment to which hematopoietic precursors are attracted and where they locally differentiate into fully mature, LTalpha(1)beta(2) expressing, LTi cells. Furthermore, the same signals may regulate lymphangiogenesis to the lymph node through induction of VEGF-C.

A plant-derived ligand favoring monomeric glucocorticoid receptor conformation with impaired transactivation potential attenuates collagen-induced arthritis.

The glucocorticoid receptor (GR) is a transcription factor regulating its target genes either positively, through direct binding to the promoter of target genes, or negatively by the interference with the activity of transcription factors involved in proinflammatory gene expression. The well-known adverse effects of glucocorticoids are believed to be mainly caused by their GR-mediated gene-activating properties. Although dimerization of GR is thought to be essential for gene-activating properties, no compound has yet been described which selectively imposes GR monomer formation and interference with other transcription factors. In the present study, we report on a GR-binding, plant-derived compound with marked dissociative properties in rheumatoid arthritis fibroblast-like synoviocytes, which are important effector cells in inflammation and matrix degradation in rheumatoid arthritis. In addition, these findings could be extended in vivo in murine collagen-induced arthritis, in which joint inflammation was markedly inhibited without inducing hyperinsulinemia. Therefore, we conclude that GR monomers are sufficient for inhibition of inflammation in vivo.

A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner.

The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) has been shown to be a potent activator of invariant NKT (iNKT) cells, rapidly inducing large amounts of both Th1 and Th2 cytokines upon injection in mice. The C-glycoside analog of alpha-GalCer (alpha-C-GalCer), by contrast, results in an enhanced Th1-type response upon activation of iNKT cells. We administered a single dose of these Ags to DBA/1 mice during the early induction phase of collagen-induced arthritis and demonstrated therapeutic efficacy of alpha-GalCer when administered early rather than late during the disease. Surprisingly, the Th1-polarizing analog alpha-C-GalCer also conferred protection. Furthermore, a biphasic role of IFN-gamma in the effect of iNKT cell stimulation was observed. Whereas in vivo neutralization of IFN-gamma release induced by either alpha-GalCer or alpha-C-GalCer early during the course of disease resulted in partial improvement of clinical arthritis symptoms, blockade of IFN-gamma release later on resulted in a more rapid onset of arthritis. Although no phenotypic changes in conventional T cells, macrophages, or APCs could be detected, important functional differences in T cell cytokine production in serum were observed upon polyclonal T cell activation, 2 wk after onset of arthritis. Whereas alpha-GalCer-treated mice produced significantly higher amounts of IL-10 upon systemic anti-CD3 stimulation compared with PBS controls, T cells from alpha-C-GalCer-treated mice, by contrast, produced substantially lower levels of cytokines, suggesting the involvement of different protective mechanisms. In conclusion, these findings suggest long-term, ligand-specific, time-dependent, and partially IFN-gamma-dependent immunomodulatory effects of iNKT cells in collagen-induced arthritis.

A unique lymphotoxin {alpha}beta-dependent pathway regulates thymic emigration of V{alpha}14 invariant natural killer T cells.

Natural killer (NK) T cells using an invariant Valpha14 (Valpha14i) T cell receptor rearrangement form a distinct immunoregulatory T cell lineage. Several studies indicated that a NK1.1(-) Valpha14i NKT precursor cell differentiates and expands within the thymus before export to the peripheral tissues occurs. However, little is known about the signals that cause the emigration of Valpha14i NKT cells from the thymus to the periphery. Here we show that signaling of lymphotoxin (LT) alphabeta through the LTbeta receptor (LTbetaR) is indispensable for regulating peripheral but not thymic Valpha14i NKT cell numbers. Homing to and homeostatic proliferation of thymic Valpha14i NKT cells in peripheral organs, however, was not dependent on LTbetaR. Instead, our data indicate that a LTbetaR-expressing thymic stromal cell regulates the thymic emigration of Valpha14i NKT cells but not conventional T cell receptor alphabeta cells.