To evaluate a magnetic resonance imaging (MRI)-based score of disease severity for perianal fistulizing Crohn's disease (CD), 16 patients with perianal fistulizing CD underwent 1.5-T MRI before and... Show moreTo evaluate a magnetic resonance imaging (MRI)-based score of disease severity for perianal fistulizing Crohn's disease (CD), 16 patients with perianal fistulizing CD underwent 1.5-T MRI before and after infliximab therapy. MRI scores, Perianal Disease Activity Index (PDAI) and C-reactive protein (CRP) were calculated, and fistula drainage was assessed. These items were compared for responders and nonresponders. After therapy, PDAI values and CRP values decreased significantly in responders, but there were no significant differences in the M RI scores. In all responders, MRI findings were indicative of persisting active inflammation. In these patients, a relapse rate of 57% was seen. (C) 2011 Elsevier Inc. All rights reserved. Show less
Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive... Show moreMesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive properties. Recent data suggest that resting MSCs do not have significant immunomodulatory activity, but that the immunosuppressive function of MSCs has to be elicited by interferon-gamma (IFN-gamma). In this article, we assessed the effects of IFN-gamma prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-gamma and assessed their therapeutic effects in dextran sodium sulfate (DSS)- and trinitrobenzene sulfonate (TNBS)-induced colitis in mice. We found that mice treated with IMSCs (but not MSCs) showed a significantly attenuated development of DSS-induced colitis. Furthermore, IMSCs alleviated symptoms of TNBS-induced colitis. IMSC-treated mice displayed an increase in body weight, lower colitis scores, and better survival rates compared with untreated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed after administration of IMSC. We also observed that IMSCs showed greater migration potential than unstimulated MSCs to sites within the inflamed intestine. In conclusion, we show that prestimulation of MSCs with IFN-gamma enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-gamma activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo. STEM CELLS 2011;29:1549-1558 Show less
BACKGROUND AND AIMS Mesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained in... Show moreBACKGROUND AND AIMS Mesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained in experimental colitis. Clinical application of MSC for the treatment of inflammatory bowel disease (IBD) is currently under investigation in phase I-III trials in patients with past or concurrent immunomodulating therapy. However, little is known about MSC interactions with these immunosuppressive drugs. To address this issue we studied the combined effect of MSC and IBD drugs in in vitro functionality assays. METHODS The effects of azathioprine, methotrexate, 6-mercaptopurine and anti-tumor necrosis factor (TNF)-α on MSC phenotype, survival, differentiation capacity and immunosuppressive capacity were studied. RESULTS MSC exposed to physiologically relevant concentrations of IBD drugs displayed a normal morphology and fulfilled phenotypic and functional criteria for MSC. Differentiation into adipocyte and osteocyte lineages was not affected and cells exhibited normal survival after exposure to the various drugs. MSC suppression of peripheral blood mononuclear cell (PBMC) proliferation in vitro was not hampered by IBD drugs. In fact, in the presence of 6-mercaptopurine and anti-TNF-α antibodies, the inhibitory effect of this drug alone was enhanced, suggesting an additive effect of pharmacotherapy and MSC treatment. CONCLUSIONS This study demonstrates that, in vitro, MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. These findings are important for the potential clinical use of MSC in combination with immunomodulating drugs and anti-TNF-α therapy. Show less
Brakenhoff, L.K.P.M.; Heijde, D.M. van der; Hommes, D.W. 2011
Arthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for... Show moreArthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for IBD. Studies evaluating specific treatments aimed at articular manifestations in patients with IBD are rare. Although there has been considerable interest in the gut-joint axis over the last decade, the pathophysiological mechanisms driving IBD-associated arthropathy are still unknown. Recently, interest in the multidisciplinary approach to patients with IBD and arthropathy has been increasing. New research and clinical projects aimed at understanding the mechanisms of disease may advance the development of effective therapies. In this review, the pathophysiology of IBD-associated arthropathy is discussed, as well as clinical manifestations, the classification and current therapeutic strategies. Show less
Background and aims. Mesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained... Show moreBackground and aims. Mesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained in experimental colitis. Clinical application of MSC for the treatment of inflammatory bowel disease (IBD) is currently under investigation in phase I-III trials in patients with past or concurrent immunomodulating therapy. However, little is known about MSC interactions with these immunosuppressive drugs. To address this issue we studied the combined effect of MSC and IBD drugs in in vitro functionality assays. Methods. The effects of azathioprine, methotrexate, 6-mercaptopurine and anti-tumor necrosis factor (TNF)-alpha on MSC phenotype, survival, differentiation capacity and immunosuppressive capacity were studied. Results. MSC exposed to physiologically relevant concentrations of IBD drugs displayed a normal morphology and fulfilled phenotypic and functional criteria for MSC. Differentiation into adipocyte and osteocyte lineages was not affected and cells exhibited normal survival after exposure to the various drugs. MSC suppression of peripheral blood mononuclear cell (PBMC) proliferation in vitro was not hampered by IBD drugs. In fact, in the presence of 6-mercaptopurine and anti-TNF-alpha antibodies, the inhibitory effect of this drug alone was enhanced, suggesting an additive effect of pharmacotherapy and MSC treatment. Conclusions. This study demonstrates that, in vitro, MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. These findings are important for the potential clinical use of MSC in combination with immunomodulating drugs and anti-TNF-alpha therapy. Show less
Arthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for... Show moreArthropathies are a major clinical problem in patients with inflammatory bowel disease (IBD). Often it is difficult to control the articular symptoms with the anti-inflammatory strategies used for IBD. Studies evaluating specific treatments aimed at articular manifestations in patients with IBD are rare. Although there has been considerable interest in the gut-joint axis over the last decade, the pathophysiological mechanisms driving IBD-associated arthropathy are still unknown. Recently, interest in the multidisciplinary approach to patients with IBD and arthropathy has been increasing. New research and clinical projects aimed at understanding the mechanisms of disease may advance the development of effective therapies. In this review, the pathophysiology of IBD-associated arthropathy is discussed, as well as clinical manifestations, the classification and current therapeutic strategies. Show less
Background: Immune suppressant medications such as thiopurines and anti-tumor necrosis factor agents are important for maintaining disease control in most patients with inflammatory bowel diseases ... Show moreBackground: Immune suppressant medications such as thiopurines and anti-tumor necrosis factor agents are important for maintaining disease control in most patients with inflammatory bowel diseases (IBDs); however, their use has been associated with the development of malignant lymphoma. The purpose of this Dutch nationwide study was to estimate the relative risk of malignant lymphoma in IBD patients. Methods: IBD patients who developed a lymphoma between 1997 and 2004 were identified using the Dutch National Database of PALGA. Data from confirmed cases were collected from individual hospitals, including data on Epstein Barr virus (EBV). The age-adjusted 8-year incidence of malignant lymphoma in the Netherlands was retrieved from the Central Bureau of Statistics. Results: Forty-two hospitals were visited and 285 matches evaluated in the total cohort of 17,834 IBD patients. Forty-four lymphomas were observed, resulting in a relative risk of 1.27 (95% confidence interval [CI]: 0.92-1.68). Only 19 of 44 patients (43%) were exposed to azathioprine/6-mercaptopurine (AZA/6-MP). Remarkably, 92% of patients (11/12) with EBV-positive lymphoma used AZA/6-MP, in contrast to only 19% patients (4/21) with EBV-negative lymphoma, suggesting a strong relation between EBV-positive lymphoma and thiopurine use. Conclusions: This nationwide study does not suggest a significant overall increased risk for lymphoma in IBD patients. A distinct correlation between EBV-positive lymphoma and AZA/6-MP use was observed. Show less
Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue... Show moreBackground: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT. Aim: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS. Methods: MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra-or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures. Results: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype (P = 0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P = 0.02) and MMP-2 CT genotype (hazard ratio 3.5, P = 0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs. Conclusion: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT. Show less
Muncan, V.; Heijmans, J.; Krasinski, S.D.; Buller, N.V.; Wildenberg, M.E.; Meisner, S.; ... ; Brink, G.R. van den 2011
In many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mother's milk to the adult diet at the end of the suckling period. These complex... Show moreIn many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mother's milk to the adult diet at the end of the suckling period. These complex developmental changes are the result of a genetic programme intrinsic to the gut tube, but its regulators have not been identified. Here we show that transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1) is highly expressed in the developing and postnatal intestinal epithelium until the suckling to weaning transition. Intestine-specific deletion of Blimp1 results in growth retardation and excessive neonatal mortality. Mutant mice lack all of the typical epithelial features of the suckling period and are born with features of an adult-like intestine. We conclude that the suckling to weaning transition is regulated by a single transcriptional repressor that delays epithelial maturation. Show less
