Elena Sonnenberg

HDAC inhibitors in models of inflammation-related tumorigenesis

Histone deacetylase (HDAC) inhibitors have been described in detail for their anti-proliferative potency. Recently, an anti-inflammatory property was characterized in vitro and in vivo. This dual efficacy of HDAC inhibitors is highly attractive, since chronic inflammations such as ulcerative colitis are associated with an increased risk of developing carcinomas. Additionally, in models of colitis and inflammation-induced tumorigenesis inflammation as well as tumor development was significantly inhibited by HDAC inhibitor treatment. The mechanisms involved reach beyond the simple regulation of histone acetylation and deacetylation. The currently known key target structures and mechanisms mediating this dual effect will be discussed in this review.

Histone deacetylase inhibitors modulate interleukin 6-dependent CD4+ T cell polarization in vitro and in vivo.

Background: HDAC inhibitors exert anti-inflammatory properties. Results: ITF2357 shifts the balance from Th17 cells toward regulatory T cells via suppression of the IL-6R expression on naïve T cells. Conclusion: The HDAC inhibitor ITF2357 modulates T cell polarization in experimental colitis. Significance: Learning the mode of action of this compound class will serve to optimize future therapeutic strategies. Histone deacetylase (HDAC) inhibitors have been associated primarily with an anti-proliferative effect in vitro and in vivo. Recent data provide evidence for an anti-inflammatory potency of HDAC inhibitors in models of experimental colitis. Because the balance of T cell subpopulations is critical for the balance of the mucosal immune system, this study explores the regulatory potency of HDAC inhibitors on T cell polarization as a mechanistic explanation for the observed anti-inflammatory effects. Although HDAC inhibition suppressed the polarization toward the pro-inflammatory T helper 17 (Th17) cells, it enhanced forkhead box P3 (FoxP3)+ regulatory T cell polarization in vitro and in vivo at the site of inflammation in the lamina propria. This was paralleled by a down-regulation of the interleukin 6 receptor (IL-6R) on naïve CD4+ T cells on the mRNA as well as on the protein level and changes in the chromatin acetylation at the IL6R gene and its promoter. Downstream of the IL-6R, HDAC inhibition was followed by a decrease in STAT3 phosphorylation as well as retinoic acid receptor-related orphan receptor γT (RORγT) expression, thus identifying the IL-6/STAT3/IL-17 pathway as an important target of HDAC inhibitors. These results directly translated to experimental colitis, where IL-6R expression was suppressed in naïve T cells, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals, resulting in the amelioration of disease. This study indicates that, in experimental colitis, inhibition of HDAC exerts an anti-inflammatory potency by directing T helper cell polarization via targeting the IL-6 pathway.

Histone deacetylase (HDAC) inhibitors modulate IL-6-dependent CD4+ T cell polarization in vitro and in vivo

Background: HDAC inhibitors exert anti-inflammatory properties. Results: ITF2357 shifts the balance from Th17 cells toward regulatory T cells via suppression of the IL-6R expression on naïve T cells. Conclusion: The HDAC inhibitor ITF2357 modulates T cell polarization in experimental colitis. Significance: Learning the mode of action of this compound class will serve to optimize future therapeutic strategies. Histone deacetylase (HDAC) inhibitors have been associated primarily with an anti-proliferative effect in vitro and in vivo. Recent data provide evidence for an anti-inflammatory potency of HDAC inhibitors in models of experimental colitis. Because the balance of T cell subpopulations is critical for the balance of the mucosal immune system, this study explores the regulatory potency of HDAC inhibitors on T cell polarization as a mechanistic explanation for the observed anti-inflammatory effects. Although HDAC inhibition suppressed the polarization toward the pro-inflammatory T helper 17 (Th17) cells, it enhanced forkhead box P3 (FoxP3)+ regulatory T cell polarization in vitro and in vivo at the site of inflammation in the lamina propria. This was paralleled by a down-regulation of the interleukin 6 receptor (IL-6R) on naïve CD4+ T cells on the mRNA as well as on the protein level and changes in the chromatin acetylation at the IL6R gene and its promoter. Downstream of the IL-6R, HDAC inhibition was followed by a decrease in STAT3 phosphorylation as well as retinoic acid receptor-related orphan receptor γT (RORγT) expression, thus identifying the IL-6/STAT3/IL-17 pathway as an important target of HDAC inhibitors. These results directly translated to experimental colitis, where IL-6R expression was suppressed in naïve T cells, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals, resulting in the amelioration of disease. This study indicates that, in experimental colitis, inhibition of HDAC exerts an anti-inflammatory potency by directing T helper cell polarization via targeting the IL-6 pathway.

Impact of Infliximab and Cyclosporine on the Risk of Colectomy in Hospitalized Patients with Ulcerative Colitis Complicated by Cytomegalovirus-A Multicenter Retrospective Study.

Background: Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA]). Methods: This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral—if treated with antivirals alone; combined—if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months. Results: A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy. Conclusions: IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.

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.

Effectiveness and Safety of Vedolizumab in Anti-TNF-Naïve Patients With Inflammatory Bowel Disease—A Multicenter Retrospective European Study

Background Vedolizumab (VDZ) is effective for treatment of ulcerative colitis (UC) and Crohns disease (CD). In GEMINI trials, anti-tumor necrosis factor (anti-TNF)-naïve patients had a superior response compared with anti-TNF-exposed patients. In real-world experience (RWE), the number of included anti-TNF-naïve patients was low. We aimed to evaluate the effectiveness and safety of VDZ in anti-TNF-naïve patients in an RWE setting. Methods This retrospective multicenter European pooled cohort study included consecutive active anti-TNF-naïve IBD patients treated with VDZ. The primary end point was clinical response at week 14. Patients with follow-up beyond week 14 and those discontinuing VDZ at any time were included for maintenance outcomes analysis. Results Since January 2015, 184 anti-TNF-naïve patients from 23 centers initiated VDZ treatment (Crohns disease [CD], 50; ulcerative colitis [UC], 134). In CD, 42/50 (82%) patients responded by week 14 and 32 (64%) were in clinical remission; 26/50 (52%) achieved corticosteroid-free remission (CSFR). At last follow-up (44 weeks; interquartile range [IQR], 30-52 weeks), 27/35 (77.1%) patients with available data responded to treatment; 24/35 (68.6%) were in clinical remission, 21/35 (60%) were in CSFR. For UC, 116/134 (79.1%) responded to treatment by week 14, including 53 (39.5%) in clinical remission; 49/134 (36.6%) achieved CSFR. At last follow-up (42.5 weeks; IQR, 30-52 weeks), 79/103 (76.7%) patients responded to treatment, 69/103 (67.0%) were in remission, and 61/103 (59.2%) were in CSFR. Adverse effects were reported in 20 (11%) of the patients, leading to treatment discontinuation in 6 (3.3%). Conclusions VDZ is similarly effective in ant-TNF-naïve CD and UC patients. The efficacy is higher than reported in anti-TNF-experienced patients and is comparable to that of anti-TNF biologics in this population.

1094 The Impact of HDAC Inhibition On CD4+ T Cells in Chronic Intestinal Inflammation

group, consisting of 10 wild-type mice. We induced a mild colitis through administration of 1.5% Dextran Sodium Sulphate (DSS) in their drinking water for 7 days. On day 8 we sacrificed the mice and scored blood loss and stool consistency. The average of the scores for weight loss, blood loss and stool consistency was defined as the disease activity index. A pathologist examined the degree of inflammation by scoring influx of inflammatory cells, crypt loss, ulceration, fibrosis, edema and the area involved. Neutrophils, macrophages and T-cells were stained using standard immunohistochemical techniques and counted. Results: The PI3Kγ-kinase-dead mice developed a significantly milder colitis than the control group. On day 8 they had gained 1.1% ± 0.9% weight, whereas the wild-type mice had lost 1.4% ± 0.6% weight, P=0.027. Their disease activity index was lower than control mice (0.63 ± 0.14, versus 1.63 ± 0.24, P=0.002). They also scored better on the histology-parameters (0.8 ± 0.1, versus 1.1 ± 0.1, P=0.02). Influx of T-cells and macrophages was significantly reduced in the PI3Kγ-kinase-dead mice (7.9 ± 0.6 versus 10.5 ± 0.9 positive cells per intercrypt area, P=0.02, and 8.7 ± 0.9, versus 11.1 ± 0.8 positive cells per intercrypt area, P=0.03, respectively). Conclusions: These data show that mice lacking functional PI3Kγ develop less severe colitis upon induction with DSS. These results suggest that the reduced influx of inflammatory cells could play an important role in this outcome and that inhibition of PI3Kγ might be a valuable target in the treatment of IBD.