Donata Lissner

Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic Intestinal Inflammation in IBD

Background:Macrophages are key players in inflammatory bowel diseases (IBD). This study aimed to determine site-specific effects of defined macrophage subtypes on the integrity of the intestinal epithelial barrier. Methods:Macrophage subtypes in situ in intestinal specimens of patients with IBD were visualized by immunohistochemistry. In vitro polarization of human peripheral CD14+ cells yielded M1 or M2 macrophages. The influence of primary monocytes or macrophage subtypes on epithelial barrier integrity was analyzed by transepithelial resistance measurements, Western blot analysis, confocal laser scanning microscopy, and cytometric bead array in a coculture model of primary human macrophages and layers of intestinal epithelial cell lines. Results:The lamina propria of the inflamed intestine in patients with IBD, predominantly in Crohns disease, is massively infiltrated by CD68+ cells also positive for inducible nitric oxide synthase and tumor necrosis factor (TNF) &agr;. The presence of M1 macrophage shifted the balance in the local macrophage compartment towards a proinflammatory state. In the coculture model, monocytes and M1 macrophages reduced transepithelial resistance as a marker for epithelial barrier integrity. The mechanisms for paracellular leakage included intracellular relocalization of tight junction proteins like claudin-2 and epithelial cell apoptosis. Determined by specific cytokine blockade, M1 macrophages exerted their deleterious effect mainly through TNF-&agr;, whereas monocyte-mediated damage was driven by the inflammasome effector cytokines, interleukin-1&bgr; and interleukin-18. Conclusions:Lamina propria monocytes and M1 macrophages invading intestinal tissues directly contribute to disrupting the epithelial barrier through deregulation of tight junction proteins and induction of epithelial cell apoptosis, thus driving intestinal inflammation in IBD.

The Multifaceted Role of the Inflammasome in Inflammatory Bowel Diseases

Inflammasomes are intracellular multiprotein complexes that coordinate the maturation of interleukin (IL)-1β and IL-18 in response to pathogens and metabolic danger. Both cytokines have been linked to intestinal inflammation. However, recently evolving concepts ascribe a major role to the inflammasome in maintaining intestinal homeostasis. This review recapitulates its position in the development of inflammatory bowel disease, thereby outlining a model in which hypo- as well as hyperfunctionality can lead to an imbalance of the system, depending on the specific cell population affected. In the epithelium, the inflammasome is essential for regulation of permeability and epithelial regeneration through sensing of commensal microbes, while excessive inflammasome activation within the lamina propria contributes to severe intestinal inflammation.

Ulcerative Colitis: Current and Future Treatment Strategies

Since the incidence of inflammatory bowel diseases including ulcerative colitis is continuously increasing worldwide, there is a strong need for effective treatment strategies. However, there is no therapy allowing for healing ulcerative colitis; consequently, the available medications will have to be applied at their best. The preferred option for mild pan- or left-sided colitis is still mesalazine. One can only emphasize that the formulations allowing for once daily dosing are not only equally effective, but even facilitate the implication of long-term therapy in daily life. In case steroids are frequently required to control disease, further immunosuppressive therapy should be introduced in order to minimize steroid exposure. Thiopurines represent the first-choice immunosuppressive medication. In more severe cases, early escalation to combinatory therapies with anti-TNF antibodies should be considered with the possibility of therapy deescalation after induction of remission. Major difficulties arise with steroid-refractory acute flares. Here cyclosporine as well as anti-TNF strategies can be initiated. However, in case of severe disease, the high 1-year colectomy rate of about 50% should be considered. If short-term surgery is an option due to disease severity, cyclosporine might be advantageous since the half-life is short compared to infliximab or adalimumab. The central problem of all therapeutic approaches is that because we chase after the disease, solid markers that allow for prediction of the future disease course are desirable. In fact, the CD8+ transcriptome might fill this gap and will potentially lead to the classification of patients in low- and high-risk groups.

Pulmonary Manifestation of Crohn’s Disease Developed Under Treatment With Vedolizumab

To the Editor: Extraintestinal, especially skinand joint-related symptoms in patients receiving the α 4β 7-antibody vedolizumab are common, with aff ected patients interestingly being those who respond excellently to therapy ( 1,2 ). Th e underlying mechanism is not clarifi ed yet. We report here on a 28-year-old male with at that time assumed ulcerative pancolitis presenting with dyspnea and dry cough aft er the third infusion of vedolizumab. He had responded well regarding his intestinal symptoms, but chest X-ray and CT-scan showed bilateral pulmonary infi ltrates with hilar lymphadenopathy ( Figure 1a ). Extensive work-up identifi ed no infectious or other specifi c cause. Tissue obtained during thoracoscopic wedge resection revealed chronic fi brosing infl ammation with characteristic noncaseating epithelioid cell-granulomas in pleura and lung with adjacent cryptogenic organizing pneumonia pattern, consistent with pleural and pulmonary manifestation of CD ( Figure 1b ). Ileocolonoscopy now revealed macroscopically non-infl amed mucosa with histological evidence of noncaseating granulomas. Th us, histopatholConsideration should be given to screen for NAFLD early on in young individuals with growth hormone alterations.

Are Immunosuppressants Becoming Obsolete

Historically, in the 1950s, the introduction of simple, old-fashioned steroids resulted in a significant drop in mortality and hence offered for the first time a real therapeutic option for patients with inflammatory bowel disease. However, as we are all aware of, steroids are no option for maintenance of remission. This review will provide an overview of the available data on the current role of azathioprine in the therapy of Crohns disease. Based on several controlled trials, the place of azathioprine for maintenance of remission is indisputable. Data from a pediatric cohort suggested that early introduction of azathioprine is beneficial for the disease course. Two recent studies aimed at reproducing these data in adult populations and failed. Hence indicating that azathioprine should only be introduced for maintenance of remission in a step-up-wise approach. An additional role for azathioprine in combo therapy with TNF antibodies has been indicated by several trials revealing a substantial benefit on response. This is partly attributed to the gain in the therapeutic effect by azathioprine itself and possibly through reduction of anti-drug antibody development. In summary, the current role of azathioprine in the therapy of Crohns disease is manifold and still has an impact in times of targeted therapy.

P014 The inflammasome induces macrophage-mediated disruption of the epithelial barrier

and ER-alpha expression, Ki-67 and Tunel were evaluated by immunohystochemical methods. Results: ER-beta, ER-alpha expression and their ratio, assessed in normal mucosa, in UC and in UC-dysplasia, did not show significant changes while in UC-carcinoma revealed a dramatic fall of ER-beta expression (p < 0.01) and still more ER-beta/ERalpha (p < 0.005). Apoptosis and Tunel/Ki-67 ratio demonstrated a statistically significant progressive increase from UC to UCcarcinoma through UC-dysplasia. Conclusions: Our experience assessed modifications of ERs expression, apoptosis and cell proliferation in dysplasiacarcinoma sequence in the course of UC. We observed a dramatic fall of ER-beta, ER-beta/ER-alpha and a progressive increase of apoptosis in progressive steps from long-lasting UC to UC-carcinoma. As observed in adenoma model, the ERbeta drop could be a biomarker of dysplasia progression and a relevant point in the study of carcinogenesis in the course of UC. Further studies are warranted.