M Neurath

Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease.

BACKGROUND Crohns disease is a chronic inflammatory disease of the alimentary tract. Azathioprine is an effective agent in the management of chronic active Crohns disease leading to long term remission of disease activity. Such treatment leads to limited efficacy or side effects in a small subset of patients. AIMS To compare efficacy and side effects of treatment with azathioprine plus corticosteroids versus mycophenolate mofetil (MMF) plus corticosteroids in patients with chronic active Crohns disease. METHODS Seventy patients with chronic active Crohns disease (Crohns disease activity index (CDAI) greater than 150) were randomised for treatment with azathioprine/cortisone or MMF/cortisone. Corticosteroid dosage was tapered according to a standard protocol. Disease activity was monitored by clinical scores after one, two, three, and six months. RESULTS Treatment of patients with moderately active (CDAI 150-300) Crohns disease with MMF/cortisone led to a significant reduction in clinical activity scores comparable to treatment with azathioprine/cortisone. Treatment of patients with highly active Crohns disease (CDAI greater than 300) with MMF/cortisone caused significant suppression of clinical activity earlier than azathioprine/cortisone treatment. Treatment with MMF/cortisone was associated with few adverse effects. CONCLUSION Treatment of chronic active Crohns disease with MMF plus cortisone appears to be effective and well tolerated and should be considered in patients allergic to azathioprine or in whom azathioprine has failed.

Interleukin-12 Production by Dendritic Cells

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.

The role of BSAP in immunoglobulin isotype switching and B-cell proliferation.

A role for the transcription factor B cell-specific activator protein (BSAP) in switch recombination has been proposed because binding sites for this protein have been found near switch regions of several isotypes. We have attempted to assess BSAPs role by altering the expression of this protein in B cells switching in culture to IgG1. We found that a phosphorothioate oligonucleotide antisense to the BSAP translation initiation site was able, when incubated with B cells, to decrease BSAP activity in nuclear extracts, and that IgG1 expression was reduced in such cells compared to cells incubated with control oligonucleotides. However, it is not clear whether this apparent reduction in switch recombination was mediated by the known BSAP binding sites in the immunoglobulin heavy chain locus because the antisense experiments revealed an additional activity of this protein: it is a rate-limiting regulator of cell proliferation. Down-regulation of BSAP was associated with decreased proliferation, while increasing BSAP (by transfection with a BSAP expression plasmid) increased proliferation. Thus because switch recombination apparently requires cell division, the effect of BSAP down-regulation on switching might have resulted from decreased proliferation. The role of BSAP in B cell proliferation suggests that dysregulation of this protein could contribute to neoplastic transformation of B cells. Because of BSAPs many activities, experiments to elucidate the mechanisms of its effects on switching and proliferation will be challenging.

Accuracy of the Full Spectrum Endoscopy (FUSE) system for assessment of disease activity in inflammatory bowel diseases (IBD) compared to high-definition endoscopy

Introduction: Recently, Full Spectrum Endoscopy (FUSE) was introduced as a novel colonoscopy platform. In contrast to other endoscopy systems illumination with the FUSE system is achieved by Light-Emitting Diodes (LEDs) and not by a xenon light source. Currently, the FUSE-system does not provide high-defi nition imaging yet. In patients with IBD, precise assessment of disease activity (i.e. mucosal healing) is of paramount importance to predict disease outcome and to guide therapy. Aims: To determine in a comparison study whether FUSE has the potential to assess disease activity in patients with IBD in comparison to a matched cohort of patients undergoing High-Defi nition White-Light Endoscopy (HD-WLE). Materials & methods: Consecutive patients with IBD (n=34) undergoing FUSE colonoscopy were matched to patients with IBD undergoing HD-WLE at the same endoscopy unit. The mucosal vascular pattern and any mucosal abnormalities were recorded. Infl ammation in ulcerative colitis was recorded according to Mayo Ulcerative Endoscopic Score (MUES) and in Crohn ́s disease according to Crohn ́s Disease Endoscopic Index of Severity (CDEIS). Subsequent to endoscopic characterization targeted biopsies were obtained for histopathological analysis of disease activity. Results: 90 cases were included. Mean age of patients was 37 years (Range 18 to 72 years). 59% of patients had diagnosis of Crohn’s disease and 41% diagnosis of ulcerative colitis. Accuracy of FUSE and HD-WL endoscopy for diagnosis of disease activity in IBD was not statistically signifi cant different (83.8% versus 71.7%). The PPV and NPV for FUSE and HD-WLE did not differ signifi cantly. In the subgroup analysis FUSE and HD-WLE endoscopy yielded in underdiagnosis and overdiagnosis of disease activity in 57% versus 46% and 43% versus 54% of not correctly predicted cases, respectively. Overall, FUSE was more accurate for diagnosis of disease activity in Crohn’s disease patients, while HD-WL endoscopy was more accurate for diagnosis of disease activity in ulcerative colitis. Conclusion: Despite the use of LEDs resulting in a darker image and high-resolution imaging, the FUSE seems to be equally effective to high-defi nition white-light imaging for diagnosis of disease activity in patients with IBD. Research Article Accuracy of the Full Spectrum Endoscopy (FUSE) system for assessment of disease activity in Infl ammatory Bowel Diseases (IBD) compared to high-defi nition endoscopy Heinz Albrecht1*, Michael Vieth2, Gian Eugenio Tontini3 and Helmut Neumann4 1Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany 2Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany 3Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy 4First Medical Department, University Medical Center Mainz, Mainz, Germany Received: 01 November, 2019 Accepted: 30 December, 2019 Published: 31 December, 2019 *Corresponding author: Heinz Albrecht, MD, Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany, E-mail: ORCID: https://orcid.org/0000-0001-7456-1079 https://www.peertechz.com