0000000000303526
AUTHOR
Raja Atreya
Review article: in vivo imaging by endocytoscopy
Aliment Pharmacol Ther 2011; 33: 1183–1193 Summary Background Endocytoscopy (EC) enables in vivo microscopic imaging at 1400-fold magnification, thereby allowing the analysis of mucosal structures at the cellular level. In contrast to fluorescence imaging with confocal laser endomicroscopy which allows analysis of mucosal structures up to 250 μm in depth, EC is based on the principle of contact light microscopy and only allows visualisation of the very superficial mucosal layer. Aim To systematically review the feasibility and diagnostic yield of EC for in vivo diagnosis of diseases. Methods A systematic search of the literature on diagnostic interventions in the gastrointestinal tract u…
Ausbildung am Ultraschallsimulator – Analyse der größten simulatorbasierten Fortbildung in Deutschland
Teaching ultrasound (US) has not been sufficiently standardised yet. Most educational devices in US consist of 2-dimensional B-mode images. However, the identification of anatomic structures in the 3-dimensional space can only be learned by practical hands-on education. In US simulators, US images of real pathologies are created by the examination of a dummy with a mock transducer. The resulting US images were previously recorded in a 3-dimensional format and were processed in a way which facilitates the reconstruction and projection of the images on a screen corresponding to the sectional plane of the mock transducer, simulating the conventional B-mode images. This enables standardised, re…
Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses
Signal transduction in response to interleukin-6 (IL-6) requires binding of the cytokine to its receptor (IL-6R) and subsequent homodimerization of the signal transducer gp130. The complex of IL-6 and soluble IL-6R (sIL-6R) triggers dimerization of gp130 and induces responses on cells that do not express membrane bound IL-6R. Naturally occurring soluble gp130 (sgp130) can be found in a ternary complex with IL-6 and sIL-6R. We created recombinant sgp130 proteins that showed binding to IL-6 in complex with sIL-6R and inhibited IL-6/sIL-6R induced proliferation of BAF/3 cells expressing gp130. Surprisingly, sgp130 proteins did not affect IL-6 stimulated proliferation of BAF/3 cells expressing …
Mongersen, an oral SMAD7 antisense oligonucleotide, and crohn's disease
Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activit…
Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14⁺ macrophages.
Background & Aims The anti–tumor necrosis factor (TNF) antibodies infliximab, adalimumab, and certolizumab pegol have proven clinical efficacy in Crohn's disease. Here, we assessed the effects of anti-TNF antibodies on apoptosis in inflammatory bowel disease (IBD). Methods CD14 + macrophages and CD4 + T cells were isolated from peripheral blood and lamina propria mononuclear cells from patients with IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and fluorescence-activated cell sorting techniques. Results Lamina propria CD14 + macrophages showed significantly more frequent and higher membrane-bound TNF (mTNF) expression than CD4 + T cells in IBD…
The transcription factor IFN regulatory factor–4 controls experimental colitis in mice via T cell–derived IL-6
The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor-4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3+ T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a mouse model of IBD whereby colitis is induced in RAG-deficient mice by transp…
Signaling molecules: the pathogenic role of the IL-6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer.
Although the precise etiology of inflammatory bowel diseases (IBD) still remains unclear, considerable progress has been made in the identification of novel signal transduction pathways that elucidate the immunopathogenesis involved in the perpetuation of the inflammatory process. As both ulcerative colitis and Crohn's disease are associated with an increased risk for developing colorectal cancer (CRC) and precancerous dysplastic epithelial changes, further studies have concentrated on finding a common signaling pathway that could serve as a mechanistic link between inflammation and associated colonic cancer in IBD. This review presents the current data concerning the pathogenic role of the…
Involvement of IL-6 in the Pathogenesis of Inflammatory Bowel Disease and Colon Cancer
Inflammatory bowel disease (IBD), which consists of Crohn’s disease and ulcerative colitis, is defined as a chronic inflammation of the gastrointestinbal tract. The etiopathogenetic mechanisms underlying the development of IBD are still not completely understood, and the therapeutic strategies used thus far have been limited to mostly evidence-based principles. There is growing evidence that the pro-inflammatory cytokine interleukin (IL)-6 plays a crucial part in the uncontrolled intestinal inflammatory process, which is a main characteristic of IBD. There is elevated production of IL-6 and its soluble receptor (sIL-6R) by intestinal macrophages and CD4+ T-cells. The increased formation of …
Novel Signal Transduction Pathways: Analysis of STAT-3 and Rac-1 Signaling in Inflammatory Bowel Disease
Although the precise etiology of inflammatory bowel disease still remains unclear, considerable progress has been made in the identification of novel signal transduction pathways that elucidate the immunopathogenesis involved in the perpetuation of the inflammatory process. Augmented T cell resistance against apoptosis is regarded as a pivotal factor in the pathogenesis, as it impairs mucosal homeostasis and leads to unrestrained accumulation of activated T cells, which subsequently lead to the amplification of the inflammatory response. Therefore novel therapeutic strategies aim at restoring mucosal T cell susceptibility to apoptosis through targeting of signal transduction pathways that a…
NF-κB in inflammatory bowel disease
Apart from genetic and environmental factors, the mucosal immune system of the gut plays a central role in the pathogenesis of inflammatory bowel disease (IBD). In the healthy gut, the mucosal immune system ensures the balance between pro- and anti-inflammatory mediators and thereby allows an effective defence against luminal pathogens but at the same time prevents an overwhelming immune reaction directed against the huge amount of harmless luminal antigens (for example, components of food or nonpathological bacteria). In both entities of IBD (Crohn's disease and ulcerative colitis) this immunological balance is severely impaired and shifted towards the pro-inflammatory side. The chronic mu…
VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer.
Inflammation drives expression of VEGFR2, which is expressed on and drives growth of tumor cells in colitis-associated cancer.
Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases.
Background and Aims: The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD]. Methods: Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potenti…
Exacerbation of ulcerative colitis after rituximab salvage therapy
Background: B-cells are considered to play a pathogenic role in human ulcerative colitis (UC) by producing autoantibodies that cause epithelial cell damage. Here we report on a patient with intractable UC who suffered from a severe exacerbation of UC after salvage therapy with rituximab, a B-cell-depleting anti-CD20-antibody. Methods: A 58-year-old patient with active long-standing UC and unresponsiveness or adverse events to mesalamine, corticosteroids, azathioprine, methotrexate, infliximab, leukapheresis, mycophenolate mofetil, and adalimumab received 375 mg/m2 rituximab. Results: A severe exacerbation of UC activity was noted upon therapy that required hospitalization. Subsequent studie…
Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo
The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppr…
CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes
Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific block- ade of Rac1 activation thro…
Future Trends in Confocal Laser Endomicroscopy: Improved Imaging Quality and Immunoendoscopy
Confocal laser endomicroscopy (CLE) is a powerful new technique that permits subsurface imaging at high resolution during ongoing endoscopy in the upper and lower GI tract [1]. Here, we will discuss future trends in CLE and their potential application in clinical practice. In particular, we will focus on molecular imaging using labelled antibodies for immunoendoscopy.
Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.
Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4–producing T cells in vitro and in vivo by an antisense ph…