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Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF–activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell–induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn’s disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.

Ulcerative colitis increases the risk of developing dysplasia and colitis-associated cancer (CAC). The purpose of this study was to determine the risk factors as well as protective measures for disease burden, need for colectomy and the development of CAC in ulcerative colitis (UC) patients. A cohort of n = 434 UC patients was evaluated. Data analysis was performed by univariate and multivariate logistic regression. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated, and significance was assessed by the likelihood ratio test. Mean patient age at UC diagnosis was 45.7 ± 15.1 years which manifested mainly as pancolitis (47 %) or left-sided colitis (45.2 %). CAC was detected in ten patients (2.3 %). UC disease duration was strongly associated with the risk of CAC (P

cope In previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis. Methods and Results Colitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil-depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity. Conclusion Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD).

Although endoscopic ultrasound (EUS) has improved the diagnostic of potential malignancies, gastric lesions with suspicion of gastrointestinal stromal tumors (GIST) or benign lesions like lipoma or leiomyoma can often not be accurately differentiated by EUS, therefore, requiring tissue sampling with the risk of bleeding complications especially in GIST. As with the newest generation of EUS machines, contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) has become a new option to determine perfusion characteristics. The aim of this analysis was to evaluate whether CEH-EUS may help to discriminate various submucosal lesions.Data sets of 17 patients with suspicious gastric or esophageal lesions, who were investigated with CEH-EUS were analyzed. Perfusion characteristics were classified by the investigator immediately and statistically analyzed after investigation. Samples from EUS-fine needle aspirates, biopsy samples after needle cut or surgical specimen served as gold standard.CEH-EUS showed nine lesions with reduced contrast enhancement (maximum intensity 6.2 ± 1.9 db) and eight lesions with hyperenhancement (47.3 ± 11.6 db). The latter eight lesions were all histologically identified as GIST, while the nine hypoenhanced lesions emerged to be four lipoma and five leiomyoma. Statistical analysis corresponded with initial perfusion classification in all cases.This is the first study showing that CEH-EUS can discriminate GIST from benign lesions with good accuracy. In the future, CEH-EUS-guided discrimination may lead to individualized diagnostic and therapeutic strategies in handling submucosal lesions.

The role of cytomegalovirus (CMV) infection in the pathogenesis and exacerbation of Inflammatory Bowel Disease (IBD) has been unresolved. Typically, the CMV genome remains dormant in infected cells, but a breakdown of immune surveillance can lead to re-activation of viral replication in the gut mucosa, which is not necessarily associated with viremia or changes in antibody titers. We hypothesized that the detection of CMV-specific CD8 effector T cells should permit the distinction between dormant and active CMV infection. As CD8 effector T cells, unlike memory CD8 T cells, have perforin (PFN) and granzyme B (GzB) preformed in their cytoplasmic granules, we employed single cell resolution ELISPOT assays to measure the CMV antigen-triggered release of these molecules by CD8 T cells isolated from subjects with IBD, and age-matched healthy controls. The frequencies of CMV-specific (GzB) and PFN-producing CD8 T cells were increased in IBD patients compared to healthy controls. Furthermore, the increased CMV reactivity was associated with active IBD disease and with longer disease duration. Notably, PCR on serum frequently failed to detect CMV DNA during flares. The data show that during active IBD there is a flare of CD8 T cell activity against CMV in a substantial proportion of IBD patients, suggesting CMV reactivation that serum PCR does not detect. While it remains open whether CMV reactivation is a cause or consequence of IBD, our data suggest that monitoring CMV antigen-specific effector CD8 T cells with GzB and PFN ELISPOT analysis can provide novel insights into the role of CMV infection in IBD. Additionally, our data have implications for the fields of transplantation, HIV, cancer, and autoimmune diseases, in all of which patient care critically depends on sensitive and reliable detection of a reactivation of CMV infection.

Background: Despite some progress in recent years, the options for treating inflammatory bowel disease (IBD) are still dissatisfying, and surgery rates are still high. The anti-inflammatory effects of melanocortin peptides such as alpha-melanocyte-stimulating hormone (α-MSH) have been described recently in, for example, dextran sodium sulfate (DSS) colitis in mice. The aim of this study was to investigate the therapeutic potential of the melanocortin-derived tripeptide α-MSH(11–13) (KPV) and its mode of action in 2 models of intestinal inflammation. Methods: The anti-inflammatory activity of KPV was analyzed in 2 well-described models of IBD: DSS colitis, and CD45RBhi transfer colitis. Furthermore, animals expressing a nonfunctional melanocortin-1 receptor (MC1Re/e) received DSS for induction of colitis and were treated with KPV. The course of inflammation was monitored by weight loss and histological changes in the colon as well as by myeloperoxidase (MPO) activity. Results: In the DSS-colitis model, treatment with KPV led to earlier recovery and significantly stronger regain of body weight. Histologically, inflammatory infiltrates were significantly reduced in KPV-treated mice, which was confirmed by the significant reduction of MPO activity in colonic tissue after KPV treatment. Supporting these findings, KPV treatment of transfer colitis led to recovery, regain of body weight, and reduced inflammatory changes histologically. In MC1Re/e mice, KPV treatment rescued all animals in the treatment group from death during DSS colitis. Conclusions: The melanocortin-derived tripeptide KPV showed significant anti-inflammatory effects in 2 murine models of colitis. These effects seem to be at least partially independent of MC1R signaling. In conclusion, our data suggest KPV as an interesting therapeutic option for the treatment of IBD. (Inflamm Bowel Dis 2007)

The aim of our study was to compare colon capsule endoscopy (CCE) with standard colonoscopy (SC) in the assessment of mucosal disease activity and localization of inflammatory colonic mucosa in patients with known ulcerative colitis (UC).Thirteen symptomatic patients (8 males, 5 females, mean age 38.5 ± 12.0 years) with known UC (mean duration of colitis: 9.7 ± 8.1 years) and indication for endoscopy due to suspected disease activity were included. All patients underwent CCE (first generation capsule, Given Imaging Ltd., Yokneam, Israel) on day 1 followed by SC on day 2 in a single center non-randomized, non-placebo-controlled diagnostic study (NCT00837304). SC and CCE were video recorded, and analysis was independently performed by 6 experienced endoscopists. The modified Rachmilewitz score was calculated, and Wilcoxon signed-rank test was used for analysis. Difference in recognition of disease activity by the endoscopists was assessed by application of the Kruskal-Wallis test.Assessment of disease activity revealed a significantly higher Rachmilewitz score of 7.3 ± 2.9 in the SC group compared to 4.8 ± 3.4 in the CCE group. Significantly, more detection of vessel vulnerability, granulated mucosa and mucosal damage was seen by SC. Disease extension was underestimated by CCE compared to SC. Disease activity assessment by means of SC or CCE did not differ statistically between the investigators (p = 0.26 and p = 0.1, respectively). After CCE, the capsule egestion rate was 77 %. The overall acceptance of both procedures was similar.Considering the significantly different assessment of disease activity and significantly more appropriate assignment of the horizontal spread of inflammation by SC versus CCE, we recommend the preferential use of SC in the assessment of inflammation in UC patients.

Citrobacter rodentium induces an acute, self-limited colitis in mice which is histologically associated with crypt hyperplasia. The infection serves as a model for human infectious colitis induced by enteropathogenic Escherichia coli. We investigated if Balb/c mice, which had spontaneously cleared C. rodentium infection, were protected against re-infection and if resistance against intestinal infection can be systemically transferred using spleen cells. The course of infection was monitored by faecal excretion. Spleen cells, splenic CD3+ and CD4+ cells were transferred from resistant mice to non-infected recipients prior to infection. Cytokine secretion, serum and faecal antibody titres and histological disease severity were assessed. Balb/c mice were resistant against re-infection. The course of infection was shorter in mice receiving primed spleen cells, CD3+ and CD4+ cells. Transfer of CD4+ T cells from resistant mice induced gamma-interferon, interleukin (IL)-2 and IL-17 secretion and suppressed IL-10 secretion. Anti-Citrobacter serum IgG1 and IgG2a enzyme-linked immunosorbent assay OD levels were increased. Faecal IgA secretion was increased while serum IgA was suppressed in recipients of CD4+ cells. Large bowel histology showed protection from colitis in recipients of primed cells as indicated by normal colonic epithelium. In Balb/c mice, C. rodentium infection is followed by resistance, which can be transferred by CD4+ cells. Transfer of protection is associated with IL-17 secretion, enhanced serum IgG and faecal IgA secretion. This is the first study to demonstrate the mechanisms by which systemic resistance from previously C. rodentium-infected mice can be transferred to non-infected animals.