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Ren DD, Chen KC, Li SS, Zhang YT, Li ZM, Liu S, Sun YS. Panax quinquefolius polysaccharides ameliorate ulcerative colitis in mice induced by dextran sulfate sodium. Front Immunol 2023; 14:1161625. [PMID: 37415978 PMCID: PMC10321667 DOI: 10.3389/fimmu.2023.1161625] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 06/05/2023] [Indexed: 07/08/2023] Open
Abstract
This study aimed to investigate the ameliorative effect of the polysaccharides of Panax quinquefolius (WQP) on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice and to explore its mechanism. Male C57BL/6J mice were randomly divided into the control group (C), model group (DSS), positive control mesalazine (100 mg/kg, Y) group, and low (50 mg/kg, L), medium (100 mg/kg, M) and high dose (200 mg/kg, H) of WQP groups. The UC model was induced by free drinking water with 2.5% DSS for 7 days. During the experiment, the general condition of the mice was observed, and the disease activity index (DAI) was scored. The conventional HE staining was used to observe pathological changes in mice's colon, and the ELISA method was used to detect the levels of interleukin-6 (IL-6), IL-4, IL-8, IL-10, IL-1β and tumor necrosis factor-α (TNF-α) in mice's colon. The changes in gut microbiota in mice were detected by high-throughput sequencing; the concentration of short-chain fatty acids (SCFAs) was determined by gas chromatography; the expression of related proteins was detected by Western blot. Compared with the DSS group, the WQP group showed a significantly lower DAI score of mice and an alleviated colon tissue injury. In the middle- and high-dose polysaccharides groups, the levels of pro-inflammatory cytokines IL-6, IL-8, IL-1β and TNF-α in the colonic tissue were significantly decreased (P<0.05), while the levels of IL-4 and IL-10 were significantly increased (P<0.05). The 16S rRNA gene sequencing results showed that different doses of WQP could regulate the composition and diversity of gut microbiota and improve its structure. Specifically, at the phylum level, group H showed an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes compared with the DSS group, which was closer to the case in group C. At the family level, the relative abundance of Rikenellaceae in L, M and H groups increased significantly, close to that in group C. At the genus level, the relative abundance of Bacteroides, Shigella and Oscillospira in the H group increased significantly, while that of Lactobacillus and Prevotella decreased significantly. The high-dose WQP group could significantly increase the contents of acetic acid, propionic acid, butyric acid, and total SCFAs. Different doses of WQP also increased the expression levels of tight junction proteins ZO-1, Occludin and Claudin-1. To sum up, WQP can regulate the gut microbiota structure of UC mice, accelerate the recovery of gut microbiota, and increase the content of Faecal SCFAs and the expression level of tight junction proteins in UC mice. This study can provide new ideas for the treatment and prevention of UC and theoretical references for the application of WQP.
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Affiliation(s)
- Duo-duo Ren
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China
- Institute of College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China
| | | | - Shan-shan Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China
- Institute of Biological and Pharmaceutical Engineering, Jilin Agricultural Science and Technology University, Jilin, China
| | - Yan-ting Zhang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Zhi-man Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Shuang Liu
- Looking Up 9 Starry Sky Medical Research Center, Siping, China
| | - Yin-shi Sun
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China
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Kiskaddon AL, Wilsey M, Gonzalez-Gomez I, Laks J, Miles A, Carapellucci J, Asante-Korang A. Basiliximab therapy for immune-mediated bowel disease in a pediatric heart transplant patient. Pediatr Transplant 2023; 27:e14443. [PMID: 36419214 DOI: 10.1111/petr.14443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 10/17/2022] [Accepted: 11/13/2022] [Indexed: 11/25/2022]
Abstract
In pediatric patients who undergo heart transplantation, severe immune-mediated bowel disease has been reported. Management is complex, and there are little data discussing the use of basiliximab for immune-mediated bowel disease. This case report discusses a pediatric patient who developed immune-mediated bowel disease following heart transplantation and was successfully managed with basiliximab.
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Affiliation(s)
- Amy L Kiskaddon
- Department of Pharmacy, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA.,Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Balitmore, Marlyand, USA
| | - Michael Wilsey
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
| | - Ignacio Gonzalez-Gomez
- Division of Pathology, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
| | - Jessica Laks
- Heart Institute, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
| | - Alyssa Miles
- Department of Pharmacy, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
| | | | - Alfred Asante-Korang
- Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Balitmore, Marlyand, USA.,Heart Institute, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
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Goldberg R, Clough JN, Roberts LB, Sanchez J, Kordasti S, Petrov N, Hertweck A, Lorenc A, Jackson I, Tasker S, Appios A, Omer O, Parkes M, Prescott N, Jenner RG, Irving PM, Lord GM. A Crohn's Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling. J Crohns Colitis 2021; 15:2054-2065. [PMID: 34120187 PMCID: PMC8684452 DOI: 10.1093/ecco-jcc/jjab103] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS Differential responsiveness to interleukin [IL]-2 between effector CD4+ T cells [Teff] and regulatory T cells [Treg] is a fundamental mechanism of immunoregulation. The single nucleotide polymorphism [SNP] rs61839660, located within IL2RA [CD25], has been associated with the development of Crohn's disease [CD]. We sought to identify the T cell immune phenotype of IBD patients who carry this SNP. METHODS Teff and Treg were isolated from individuals homozygous [TT], heterozygous [CT], or wild-type [CC] for the minor allele at rs61839660, and used for phenotyping [flow cytometry, Cytometry Time Of Flight] functional assays or T cell receptor [TCR] sequencing. Phosphorylation of signal transducer and activator of transcription 5 [STAT5] was assessed in response to IL-2, IL-7, and in the presence of basiliximab, a monoclonal antibody directed against CD25. Teff pro-inflammatory cytokine expression levels were assessed by reverse transcription quantitative polymerase chain reaction after IL-2 and/or TCR stimulation. RESULTS Presence of the minor T allele enhances CD25 expression, leading to increased STAT5 phosphorylation and pro-inflammatory cytokine transcript expression by Teff in response to IL-2 stimulation in vitro. Teff from TT individuals demonstrate a more activated gut homing phenotype. TCR sequencing analysis suggests that TT patients may have a reduced clonal capacity to mount an optimal regulatory T cell response. CONCLUSIONS rs61839660 regulates the responsiveness of T cells to IL-2 signalling by modulating CD25 expression. As low-dose IL-2 is being trialled as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.
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Affiliation(s)
- Rimma Goldberg
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
| | - Jennie N Clough
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- IBD Unit, Gastroenterology Department, Guy’s and St Thomas’ NHS Trust, London, UK
- National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK
| | - Luke B Roberts
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK
| | - Jenifer Sanchez
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Shahram Kordasti
- CRUK-KHP Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK
| | - Nedyalko Petrov
- National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK
| | | | - Anna Lorenc
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Ian Jackson
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK
| | - Scott Tasker
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Anna Appios
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Omer Omer
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- IBD Unit, Gastroenterology Department, Guy’s and St Thomas’ NHS Trust, London, UK
| | - Miles Parkes
- Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
| | - Natalie Prescott
- National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK
- Medical and Molecular Genetics, Kings College London, London, UK
| | | | - Peter M Irving
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- IBD Unit, Gastroenterology Department, Guy’s and St Thomas’ NHS Trust, London, UK
| | - Graham M Lord
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Trust and King’s College London, London, UK
- Faculty of Biology, Medicine and Health, University of Manchester, UK
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Giuffrida P, Di Sabatino A. Targeting T cells in inflammatory bowel disease. Pharmacol Res 2020; 159:105040. [PMID: 32585338 DOI: 10.1016/j.phrs.2020.105040] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022]
Abstract
T cells play a pivotal role in the immune response underlying inflammatory bowel disease (IBD) pathogenesis. On this basis, over the past 25 years several drugs have assessed to target T cells in IBD patients. Amongst anti-CD3 antibodies, visilizumab and foralumab did not show clinical efficacy in ulcerative colitis (UC) and Crohn's disease (CD) patients, respectively, whereas otelixizumab has been tested in vitro only. The anti-CD4 BF-5 and cM-T412, and the anti-CD25 basiliximab and daclizumab were not effective in CD and UC patients, respectively. The anti-NKG2D antibody NNC0142-0002 showed clinical benefit in CD patients, in particular in biologic naïve ones, in a randomized, double-blind, parallel-group, placebo-controlled trial. The anti-CD40L M90 and the GSK1349571A blocking calcium release-activated calcium (CRAC) channels, which are involved in the T cell activation and proliferation, were tested only in ex vivo/in vitro experiments. Apart from ustekinumab, all the other drugs targeting T cell-derived cytokines failed. The reinduction of lamina propria T cell apoptosis is a mechanism to modulate T cell survival exploited by cyclosporin A, azathioprine and anti-tumor necrosis factor-α agents, such as infliximab, adalimumab and golimumab. In this article, we review the drugs targeting T cells via surface receptors, via T cell-derived cytokines, via CRAC channels or by inducing apoptosis.
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Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
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Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.
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Vandewalle J, Luypaert A, De Bosscher K, Libert C. Therapeutic Mechanisms of Glucocorticoids. Trends Endocrinol Metab 2018; 29:42-54. [PMID: 29162310 DOI: 10.1016/j.tem.2017.10.010] [Citation(s) in RCA: 335] [Impact Index Per Article: 47.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/26/2017] [Accepted: 10/27/2017] [Indexed: 12/20/2022]
Abstract
Glucocorticoids (GCs) have been used clinically for decades as potent anti-inflammatory and immunosuppressive agents. Nevertheless, their use is severely hampered by the risk of developing side effects and the occurrence of glucocorticoid resistance (GCR). Therefore, efforts to understand the complex mechanisms underlying GC function and GCR are ongoing. The goal is to generate new glucocorticoid receptor (GR) ligands that can dissociate anti-inflammatory from metabolic side effects and/or overcome GCR. In this review paper we discuss recent insights into GR-mediated actions in GCR and novel therapeutic strategies for acute and chronic inflammatory diseases.
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Affiliation(s)
- Jolien Vandewalle
- Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Astrid Luypaert
- Receptor Research Laboratories, Nuclear Receptor Lab, VIB-University of Ghent (UGent) Center for Medical Biotechnology, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium
| | - Karolien De Bosscher
- Receptor Research Laboratories, Nuclear Receptor Lab, VIB-University of Ghent (UGent) Center for Medical Biotechnology, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium
| | - Claude Libert
- Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
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Lv J, Zhang Y, Tian Z, Liu F, Shi Y, Liu Y, Xia P. Astragalus polysaccharides protect against dextran sulfate sodium-induced colitis by inhibiting NF-κВ activation. Int J Biol Macromol 2017; 98:723-729. [PMID: 28188801 DOI: 10.1016/j.ijbiomac.2017.02.024] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 01/31/2017] [Accepted: 02/06/2017] [Indexed: 01/08/2023]
Abstract
Astragalus polysaccharide (APS) is a bioactive extract of Astragalus membranaceus (AM), which possess a wide range of medicinal benefits, including anti-inflammatory, anti-oxidative, anti-tumor and anti-diabetic effects. The present work evaluated the therapeutic effect of APS and its potential mechanisms in a mouse model of dextran sulfate sodium (DSS)-induced colitis. The APS treatment led to significant improvements in colitis disease activity index (DAI) and histological scores, as well as significantly increased weight and colon length in mice as compared to the control group. Mechanically, reduced NF-κВ DNA phosphorylation activity and downregulated TNF-α, IL-1β, IL-6, IL-17 expressions and myeloperoxidase (MPO) activity were associated with improvement in colitis observed in APS-treated mice. These findings suggest that APS may represent a natural therapeutic approach for treating inflammatory bowel disease, such as ulcerative colitis.
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Affiliation(s)
- Jun Lv
- Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yahong Zhang
- Pharmaceutical Department, Chongqing Medical and Pharmaceutical College, Chongqing, 401331, China
| | - Zhiqiang Tian
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China
| | - Fang Liu
- Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ying Shi
- Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yao Liu
- Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Peiyuan Xia
- Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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Cao Y, Lu X, Wang J, Zhang H, Liu Z, Xu S, Wang T, Ning S, Xiao B, Wang L. Construction of an miRNA-regulated drug-pathway network reveals drug repurposing candidates for myasthenia gravis. Int J Mol Med 2017; 39:268-278. [PMID: 28075449 PMCID: PMC5358695 DOI: 10.3892/ijmm.2017.2853] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 01/04/2017] [Indexed: 12/31/2022] Open
Abstract
Myasthenia gravis (MG) is a rare debilitating autoimmune neuromuscular disorder. Many studies have focused on the mechanism and treatment strategies of MG. However, the exact pathogenesis of MG and effective treatment strategies remain unclear. Recent studies have indicated that microRNAs (miRNAs or miRs) can regulate the pathological pathways of MG, suggesting their potential role in novel treatments. In the present study, we created a comprehensive catalog of experimentally confirmed MG risk genes and miRNAs by manually mining published literature and public databases. Based on these genes and miRNAs, we identified 41 MG risk pathways and 105 approved drugs that can affect these pathways. Some important MG-related pathways, such as hsa04060 (cytokine-cytokine receptor interaction) and hsa05200 (pathway in cancer), were found to be regulated by MG risk miRNAs and drugs. Furthermore, we constructed an miRNA-regulated drug-pathway network and identified miRNAs and drugs that synergistically regulate key MG pathways and biological processes. We developed a drug repurposing strategy to identify 25 drug repurposing candidates for MG; several of these drugs, such as rituximab, adalimumab, sunitinib, and muromonab, have the potential to be novel MG treatment drugs. This study provides novel insight into the pathogenesis of MG and potential drug candidates for MG were identified.
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Affiliation(s)
- Yuze Cao
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xiaoyan Lu
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jianjian Wang
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Huixue Zhang
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Zhaojun Liu
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Si Xu
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Tianfeng Wang
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Lihua Wang
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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Gómez-Gómez GJ, Masedo &A, Yela C, Martínez-Montiel MDP, Casís B. Current stage in inflammatory bowel disease: What is next? World J Gastroenterol 2015; 21:11282-11303. [PMID: 26525013 PMCID: PMC4616205 DOI: 10.3748/wjg.v21.i40.11282] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/12/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.
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Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, d'Haens G, d'Hoore A, Mantzanaris G, Novacek G, Öresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, van Assche G. [Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management (Spanish version)]. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2015; 80:32-73. [PMID: 25769217 DOI: 10.1016/j.rgmx.2014.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023]
Affiliation(s)
- A Dignass
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso.
| | | | - A Sturm
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - A Windsor
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - J-F Colombel
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - M Allez
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G d'Haens
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - A d'Hoore
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G Mantzanaris
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G Novacek
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - T Öresland
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - W Reinisch
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - M Sans
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - E Stange
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - S Vermeire
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - S Travis
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
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11
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Chun J, Lee C, Kwon JE, Hwang SW, Kim SG, Kim JS, Jung HC, Im JP. Usefulness of the cytomegalovirus antigenemia assay in patients with ulcerative colitis. Intest Res 2015; 13:50-9. [PMID: 25691843 PMCID: PMC4316222 DOI: 10.5217/ir.2015.13.1.50] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 05/28/2014] [Accepted: 06/30/2014] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Patients with ulcerative colitis (UC) are at high risk for cytomegalovirus (CMV) reactivation. The usefulness of the CMV antigenemia assay in active UC patients has rarely been studied. We assessed whether the assay detects CMV colitis and predicts clinical outcomes in patients with UC. Methods We retrospectively reviewed the medical records of patients hospitalized for moderate-to-severe UC from 2003 to 2012. Positive CMV antigenemia was defined as ≥1 pp65-positive cell per 2×105 polymorphonuclear neutrophils. CMV colitis was defined as the presence of inclusion bodies and/or positive immunohistochemistry in the colonic mucosa. The primary outcome was steroid refractoriness, defined as the absence of clinical improvement after intravenous high-dose steroid administration. Results A total of 43 patients were enrolled. CMV antigenemia was detected in 12 (27.9%) patients. Positive CMV antigenemia was significantly associated with CMV colitis (P =0.001). The sensitivity and specificity of positive CMV antigenemia for diagnosing CMV colitis were 66.7% and 87.1%, respectively. Steroid refractoriness was found in 11 of 12 (91.7%) and 12 of 31 (38.7%) patients with positive and negative CMV antigenemia, respectively (P =0.002). The independent predictors for steroid refractoriness were positive CMV antigenemia (adjusted odds ratio [OR], 7.73; 95% confidence interval [CI], 1.22-49.19; P =0.030) and a shorter duration from the diagnosis of UC (adjusted OR, 0.99; 95% CI, 0.98-0.99; P =0.025). Conclusions The CMV antigenemia assay shows low sensitivity but high specificity for detecting CMV colitis and may predict steroid-refractory UC. Early rescue therapy might be considered in UC patients positive for CMV antigenemia.
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Affiliation(s)
- Jaeyoung Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Changhyun Lee
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
| | - Ji-Eun Kwon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Wook Hwang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Shigeta T, Sakamoto S, Uchida H, Sasaki K, Hamano I, Kanazawa H, Fukuda A, Kawai T, Onodera M, Nakazawa A, Kasahara M. Basiliximab treatment for steroid-resistant rejection in pediatric patients following liver transplantation for acute liver failure. Pediatr Transplant 2014; 18:860-7. [PMID: 25311536 DOI: 10.1111/petr.12373] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2014] [Indexed: 01/08/2023]
Abstract
An IL-2 receptor antagonist, basiliximab, decreases the frequency of ACR in liver transplant (LT) recipients as induction therapy. The aim of this study was to evaluate the effectiveness of basiliximab against SRR as rescue therapy in pediatric LT patients with ALF. Forty pediatric ALF patients underwent LT between November 2005 and July 2013. Among them, seven patients suffering from SRR were enrolled in this study. The median age at LT was 10 months (6-12 months). SRR was defined as the occurrence of refractory rejection after more than two courses of steroid pulse therapy. Basiliximab was administered to all patients. The withdrawal of steroids without deterioration of the liver function was achieved in six patients treated with basiliximab therapy without patient mortality, although one patient developed graft loss and required retransplantation for veno-occlusive disease. The pathological examinations of liver biopsies in the patients suffering from SRR revealed severe centrilobular injuries, particularly fibrosis within one month after LT. We demonstrated the effectiveness and safety of rescue therapy consisting of basiliximab for SRR in pediatric LT recipients with ALF.
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Affiliation(s)
- Takanobu Shigeta
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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13
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Peng JC, Shen J, Ran ZH. Novel agents in the future: Therapy beyond anti-TNF agents in inflammatory bowel disease. J Dig Dis 2014; 15:585-90. [PMID: 25251263 DOI: 10.1111/1751-2980.12193] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Anti-tumor necrosis factor (TNF)-α agents emerge as the hot spot in the last decade for treating patients with inflammatory bowel disease (IBD). The effect of anti-TNF-α agents is satisfactory; however, some patients fail to achieve clinical response. Fortunately, in recent years, great efforts have been made and multiple novel therapies have been developed in the treatment for IBD. In this article, we aim to introduce anti-TNF-α drugs as well as other novel treatments currently undergoing clinical trials for IBD.
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Affiliation(s)
- Jiang Chen Peng
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai Inflammatory Bowel Disease Research Center, Shanghai, China
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14
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Abstract
BACKGROUND Ulcerative colitis (UC) is an idiopathic inflammatory disorder. Currently, the main goals of treatment are to induce and maintain clinical and/or endoscopic remission. However, evidence indicates that persistent disease activity on colonic biopsies in the setting of clinical or endoscopic remission is an independent predictor of poor outcomes. A number of previous studies have proposed histologic indices for use in specific trials of UC. The aim of this study was to systematically review the existing histological indices for UC and assess their potential use in both patient management and clinical trials. METHODS We performed a systematic review of histological indices evaluating disease activity in UC. MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Diseases Week (DDW) abstracts of randomized and/or controlled trials clinical trials were searched from inception to February 2013 for applicable studies. Data from these studies were reviewed and analyzed. RESULTS After systematically applying inclusion criteria, we identified 108 scientific articles including 88 clinical studies and 21 related clinical reviews. Eighteen indices of histological activity in UC were identified and reviewed. CONCLUSIONS Although multiple histological scoring indices for assessment of UC disease activity currently exist, none of these instruments were developed using a formal validation process and their operating properties remain poorly understood. Future studies are needed to address this deficiency.
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15
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Dominance of the strongest: inflammatory cytokines versus glucocorticoids. Cytokine Growth Factor Rev 2013; 25:21-33. [PMID: 24412262 DOI: 10.1016/j.cytogfr.2013.12.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 12/15/2013] [Indexed: 02/08/2023]
Abstract
Pro-inflammatory cytokines are involved in the pathogenesis of many inflammatory diseases, and the excessive expression of many of them is normally counteracted by glucocorticoids (GCs), which are steroids that bind to the glucocorticoid receptor (GR). Hence, GCs are potent inhibitors of inflammation, and they are widely used to treat inflammatory diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease. However, despite the success of GC therapy, many patients show some degree of GC unresponsiveness, called GC resistance (GCR). This is a serious problem because it limits the full therapeutic exploitation of the anti-inflammatory power of GCs. Patients with reduced GC responses often have higher cytokine levels, and there is a complex interplay between GCs and cytokines: GCs downregulate pro-inflammatory cytokines while cytokines limit GC action. Treatment of inflammatory diseases with GCs is successful when GCs dominate. But when cytokines overrule the anti-inflammatory actions of GCs, patients become GC insensitive. New insights into the molecular mechanisms of GR-mediated actions and GCR are needed for the design of more effective GC-based therapies.
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16
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Valatas V, Vakas M, Kolios G. The value of experimental models of colitis in predicting efficacy of biological therapies for inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol 2013; 305:G763-85. [PMID: 23989010 DOI: 10.1152/ajpgi.00004.2013] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
During the last decade, biological therapies have an increasing share in the modern therapeutics of various diseases including inflammatory bowel diseases (IBD). Animal models of IBD have often been used to identify the targets of biological therapies, to test their relevance to disease pathogenesis, to assess their therapeutic efficacy in vivo, and to check for drug toxicity. In the field of inflammatory diseases the majority of biologics under development have failed to reach the clinic. This review examines the ability of preclinical data from animal models of IBD to predict success or failure of biologics in human IBD. Specifically, it describes the murine models of IBD, the mechanism of disease induction, the phenotype of the disease, its relevance to human IBD, and the specific immunological features of disease pathogenesis in each model and mainly compares the results of the phase II and III trials of biologics in IBD with preclinical data obtained from studies in animal models. Finally, it examines the possible reasons for low success in translation from bench to bedside and offers some suggestions to improve translation rates.
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Affiliation(s)
- Vassilis Valatas
- Dept. of Gastroenterology, Univ. Hospital of Heraklion, PO Box 1352, Voutes, Heraklion, GR-71100, Crete, Greece.
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17
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Biancheri P, Powell N, Monteleone G, Lord G, MacDonald TT. The challenges of stratifying patients for trials in inflammatory bowel disease. Trends Immunol 2013; 34:564-71. [PMID: 24035478 DOI: 10.1016/j.it.2013.08.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 05/24/2013] [Accepted: 08/07/2013] [Indexed: 10/26/2022]
Abstract
Immunotherapy with biological agents or small molecules is revolutionising the treatment of chronic inflammatory disease in humans; however, a significant proportion of patients fail to respond or lose responsiveness. This is particularly evident in inflammatory bowel disease (IBD), a group of chronic, immune-mediated disorders of the gastrointestinal tract. Different responsiveness to treatment in IBD can be explained by substantial disease heterogeneity, which is being increasingly recognised by genetic and immunological studies. The current enthusiasm for stratified medicine suggests that it may become possible to identify clinical, immunological, biochemical or genetic biomarkers to target immunotherapy to patients more likely to respond. Here, we identify and highlight the opportunities and the challenges of this strategy in the context of IBD.
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Affiliation(s)
- Paolo Biancheri
- Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK
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18
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Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, D'Haens G, D'Hoore A, Mantzaris G, Novacek G, Oresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, Van Assche G. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012; 6:991-1030. [PMID: 23040451 DOI: 10.1016/j.crohns.2012.09.002] [Citation(s) in RCA: 692] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 09/03/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Axel Dignass
- Department of Medicine 1, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Germany.
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Papa A, Mocci G, Bonizzi M, Felice C, Andrisani G, Papa G, Gasbarrini A. Biological therapies for inflammatory bowel disease: controversies and future options. Expert Rev Clin Pharmacol 2012; 2:391-403. [PMID: 22112183 DOI: 10.1586/ecp.09.12] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Over the last few years, advances in understanding the pathogenesis of inflammatory bowel disease, together with progress in biotechnology, have led to the availability of several biological drugs that have dramatically changed the therapeutic approach to these disorders. Indeed, several molecules targeting crucial inflammatory cytokines, blocking T-cell activation/proliferation or the recruitment of inflammatory cells into the inflamed bowel, have been discovered and commercialized. However, the increasing use of biological agents has raised some concerns regarding their short- and long-term safety. This review offers a critical evaluation of the efficacy and safety of biological agents in the management of both Crohn's disease and ulcerative colitis. In addition, promising therapeutic options are discussed.
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Affiliation(s)
- Alfredo Papa
- Istituto di Medicina Interna e Geriatria, Policlinico A. Gemelli, Università Cattolica del S. Cuore, L.go A. Gemelli, 8 00168 Roma, Italy.
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20
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Abstract
Steroid-resistant asthma (SRA) refers to patients with symptoms consistent with asthma who show very poor or no response at all to high doses of inhaled or even of systemic corticosteroids. The current article reviews the SRA related literature focusing on the problems associated with the definition of SRA (especially its association with difficult to control, or severe asthma), its various phenotypes, its molecular basis, and the potential treatment options. The article also discusses the limitations of some of the key criteria used for the determination of SRA and proposes a modified set of criteria that are more applicable to children.
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Affiliation(s)
- Robert P Yim
- Division of Pulmonary & Sleep Medicine, Children's National Medical Center, Washington DC 20010, USA
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21
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Sands BE, Sandborn WJ, Creed TJ, Dayan CM, Dhanda AD, Van Assche GA, Greguš M, Sood A, Choudhuri G, Stempien MJ, Levitt D, Probert CS. Basiliximab does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis. Gastroenterology 2012; 143:356-64.e1. [PMID: 22549092 DOI: 10.1053/j.gastro.2012.04.043] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 04/04/2012] [Accepted: 04/19/2012] [Indexed: 01/22/2023]
Abstract
BACKGROUND & AIMS Basiliximab is a chimeric monoclonal antibody that binds CD25 and thereby inhibits interleukin (IL)-2-mediated proliferation of lymphocytes. IL-2 might contribute to the resistance of T cells to corticosteroids. We investigated the efficacy and safety of basiliximab as a corticosteroid-sensitizing agent in patients with corticosteroid-refractory ulcerative colitis (UC). METHODS We studied 149 patients with moderate to severe UC (Mayo score ≥6 and endoscopic subscore ≥2) despite treatment for at least 14 days with oral prednisone (40-50 mg/day). Subjects were randomly assigned to groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. All subjects received 30 mg/day prednisone through week 2; the dose was reduced by 5 mg each week to 20 mg/day, which was maintained until week 8. At week 8, we compared the rates of clinical remission (Mayo score ≤2, no subscore >1) for patients given basiliximab with the rate for patients given placebo. RESULTS Twenty-eight percent of patients given placebo, 29% of those given the 40-mg dose of basiliximab, and 26% of those given the 20-mg dose of basiliximab achieved clinical remission (P = 1.00 vs placebo for each dose). Basiliximab was generally well tolerated. Six subjects who received basiliximab had serious adverse events (6.1%) compared with 2 who received placebo (3.9%; P = .72). In subjects given basiliximab, incomplete saturation of CD25 (<50%) on peripheral T cells was associated with the presence of anti-basiliximab antibodies (odds ratio, 21; 95% confidence interval, 2.4-184). CONCLUSIONS Basiliximab does not increase the effect of corticosteroids in the induction of remission in outpatients with corticosteroid-resistant moderate to severe UC.
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22
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Stübgen JP. Targeted immunotherapy trials for idiopathic inflammatory myopathies. J Neurol 2012; 260:368-85. [DOI: 10.1007/s00415-012-6590-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 06/11/2012] [Accepted: 06/12/2012] [Indexed: 12/13/2022]
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Winter TA, Quan SY. Anti-inflammatories and the gastrointestinal tract: Victores et Victis. J Gastroenterol Hepatol 2012; 27:853-6. [PMID: 22515806 DOI: 10.1111/j.1440-1746.2012.07106.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Abstract
Inflammatory bowel diseases (IBDs) are chronic disabling diseases with significant morbidity. A deregulated immune response towards the intestinal microbiota is thought to play an important role in the pathogenesis of IBD, and thus biological therapies targeting key molecules such as cytokines have been designed. Several anti-TNF-α agents are currently being used to treat Crohn's disease and ulcerative colitis. Although these molecules dramatically improved the treatment of patients, side effects and the development of antidrug antibodies limits their application. There is thus an urgent need for alternative approaches to decrease inflammation and limit immunogenicity. Small neutralizing molecules, active immunization, gene silencing, selective transcription inhibitors and delivery of agents through the oral route are some of the currently developed strategies to meet these needs. In parallel, neutralizing antibodies targeting other pathways of the immune system have been developed and tested. Antibodies targeting IL-12/IL-23 pathways, and proinflammatory cytokines such as IFN-γ, IL-17A, IL-2 and IL-6 often showed an initial promising result, but for none of these agents efficacy has unequivocally been established. Administration of the regulatory cytokines IL-10 and IL-11 also failed to induce reproducible clinical effects. This article focuses on the anti-TNF therapies and the current challenges with monoclonal antibody therapies, discusses the innovative strategies targeting cytokine pathways to decrease inflammation in the bowel, and summarizes the recently developed agents neutralizing proinflammatory cytokines.
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Affiliation(s)
- Clémentine Perrier
- Division of Gastroenterology, University Hospital, Catholic University Leuven, Leuven, Belgium
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25
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The prevalence and efficacy of ganciclovir on steroid-refractory ulcerative colitis with cytomegalovirus infection: a prospective multicenter study. J Clin Gastroenterol 2012; 46:51-6. [PMID: 21552140 DOI: 10.1097/mcg.0b013e3182160c9c] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND It remains controversial whether or not cytomegalovirus infection in patients with active ulcerative colitis reflects a nonpathogenic colonization or a pathogenic disease warranting antiviral therapy. GOALS The aim of this study was to determine the prevalence of cytomegalovirus infection in patients with active ulcerative colitis and the therapeutic efficacy of ganciclovir against cytomegalovirus infection in patients with steroid-refractory ulcerative colitis. STUDY A prospective, multicenter study was conducted in 72 patients with moderate-to-severe ulcerative colitis who were treated with intravenous steroids. The presence of cytomegalovirus was evaluated serologically and histopathologic examination, including immunohistochemical staining. In patients with steroid-refractory ulcerative colitis, cytomegalovirus infections were treated with intravenous ganciclovir. In patients with steroid-responsive ulcerative colitis, steroid therapy was continued irrespective of cytomegalovirus infection. RESULTS The evidence of cytomegalovirus infection was found in 31 patients (43%) with moderate-to-severe active ulcerative colitis. In patients with steroid-refractory ulcerative colitis, the cytomegalovirus infection rate increased to 67% (14 of 21). No significant clinical and endoscopic differences existed between patients with and without a cytomegalovirus infection; however, the amount of steroids used during the flare-up period was significantly higher in patients with a cytomegalovirus infection (P = 0.013). Eleven of 14 patients (79%) with steroid-refractory ulcerative colitis and a cytomegalovirus infection improved with ganciclovir treatment. Cytomegalovirus infections in the steroid-responsive group (17 of 31) did not require ganciclovir therapy. CONCLUSIONS Cytomegalovirus infections are frequently observed in patients with moderate-to-severe ulcerative colitis, especially steroid-refractory ulcerative colitis. Ganciclovir was effective in patients with steroid-refractory ulcerative colitis who had a cytomegalovirus infection.
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Oliver-Goicolea P, Irastorza-Terradillos I, Vitoria-Cormenzana J. Tratamiento de la colitis ulcerosa fulminante refractaria con anticuerpos quiméricos anti-CD25. An Pediatr (Barc) 2011; 74:340-1. [DOI: 10.1016/j.anpedi.2010.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2010] [Revised: 12/28/2010] [Accepted: 12/28/2010] [Indexed: 11/15/2022] Open
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Maul J, Zeitz M. Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations. Langenbecks Arch Surg 2011. [PMID: 21479621 DOI: 10.1007/s00423-011-0789-4.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental and microbial factors drives chronic intestinal inflammation that finally leads to extensive tissue fibrosis. DISCUSSION The present review discusses the current knowledge on genetic susceptibility, especially of the IL-12/IL-23 pathway, the pathophysiologic role of the involved cytokines (e.g. IL-13, IL-23, TGFβ1) and immune cells (e.g. T cells, epithelial cells, fibroblasts) in UC followed by an overview on actual therapeutic considerations. These future therapies will target selectively the involved cell types by blocking their activation and its downstream signalling, by inhibiting their migration to the inflamed site and by anti-cytokine strategies. This may avoid-when initiated in time-the perpetuation of the inflammatory mechanisms thus preventing fibrosis. With respect to animal models that have guided the most productive efforts for understanding human inflammatory bowel disease, these will be shortly discussed in the respective context.
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Affiliation(s)
- Jochen Maul
- Department of Medicine I (Gastroenterology/Rheumatology/Infectious Diseases), Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200, Berlin, Germany
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Maul J, Zeitz M. Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations. Langenbecks Arch Surg 2011; 397:1-10. [PMID: 21479621 DOI: 10.1007/s00423-011-0789-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Accepted: 03/13/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental and microbial factors drives chronic intestinal inflammation that finally leads to extensive tissue fibrosis. DISCUSSION The present review discusses the current knowledge on genetic susceptibility, especially of the IL-12/IL-23 pathway, the pathophysiologic role of the involved cytokines (e.g. IL-13, IL-23, TGFβ1) and immune cells (e.g. T cells, epithelial cells, fibroblasts) in UC followed by an overview on actual therapeutic considerations. These future therapies will target selectively the involved cell types by blocking their activation and its downstream signalling, by inhibiting their migration to the inflamed site and by anti-cytokine strategies. This may avoid-when initiated in time-the perpetuation of the inflammatory mechanisms thus preventing fibrosis. With respect to animal models that have guided the most productive efforts for understanding human inflammatory bowel disease, these will be shortly discussed in the respective context.
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Affiliation(s)
- Jochen Maul
- Department of Medicine I (Gastroenterology/Rheumatology/Infectious Diseases), Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200, Berlin, Germany
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Triantafillidis JK, Merikas E, Georgopoulos F. Current and emerging drugs for the treatment of inflammatory bowel disease. DRUG DESIGN DEVELOPMENT AND THERAPY 2011; 5:185-210. [PMID: 21552489 PMCID: PMC3084301 DOI: 10.2147/dddt.s11290] [Citation(s) in RCA: 202] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Indexed: 12/14/2022]
Abstract
During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn’s disease and ulcerative colitis.
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Affiliation(s)
- John K Triantafillidis
- Department of Gastroenterology, Center for Inflammatory Bowel Disease, "Saint Panteleimon" General Hospital, Nicea, Greece.
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di Mambro AJ, Parker R, McCune A, Gordon F, Dayan CM, Collins P. In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis. Hepatology 2011; 53:1316-22. [PMID: 21400552 DOI: 10.1002/hep.24159] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2010] [Accepted: 12/21/2010] [Indexed: 12/20/2022]
Abstract
UNLABELLED Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin-2 (IL-2) exacerbates steroid resistance in vitro. We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL-2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddrey's score >32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of <25% within 7 days or death within 6 months. In vitro steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti-IL-2 receptor (anti-CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation <60% was considered to indicate steroid resistance. In all, 82% (9/11) of in vitro steroid-resistant patients were dead at 6 months as compared to 21% (2/9) of steroid-sensitive patients (P = 0.03). Similarly, 91% (10/11) of in vitro steroid-resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid-sensitive patients (P < 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of in vitro steroid-resistant patients (P = 0.003). CONCLUSION Clinical outcome of steroid therapy in this patient cohort correlated with in vitro steroid resistance. IL-2 blockade improved in vitro steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL-2 receptor blockade represents a possible mechanism to overcome this.
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Affiliation(s)
- A J di Mambro
- Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK; Department of Liver Medicine, Bristol Royal Infirmary, Bristol, UK
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Chen O, Li CP, Luo B, Feng Q, Ma CH, Feng KX. Efficacy of curcumin in the management of dextan sulphate sodium-induced ulcerative colitis in mice. Shijie Huaren Xiaohua Zazhi 2011; 19:680-686. [DOI: 10.11569/wcjd.v19.i7.680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of curcumin in the treatment of dextran sulphate sodium (DSS)-induced ulcerative colitis in mice.
METHODS: Sixty female BALB/c mice were randomly divided into four groups: normal group, experimental colitis group (administered with 5% DSS solution), curcumin treatment group (administered with 5% DSS solution and intraperitoneally injected with curcumin, 30 mg/kg body weight), dexamethasone treatment group (administered with 5% DSS solution and intraperitoneally injected with dexamethasone, 0.4 mg/kg body weight). The severity of colitis was evaluated using the disease activity index (DAI) score, and colonic mucosal histological changes were observed by HE staining. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in colonic tissue were determined by ELISA. The expression of nuclear factor-κB (NF-κB) in intestinal inflammatory cells was determined by immunohistochemistry. The expression of inhibitor of NF-κB (IκB) in intestinal inflammatory cells was determined by Western blot.
RESULTS: Compared with the normal group and experimental colitis group, treatment with curcumin significantly improved symptoms, reduced colonic DAI and histological scores (DAI: 1.64 ± 0.92, 2.80 ± 0.92 vs 7.67 ± 1.56; histological scores: 1.36 ± 0.50, 2.00 ± 0.67 vs 2.83 ± 0.83, all P < 0.01), and decreased the levels of colonic TNF-α and IL-6 (TNF-α: 102.75 ± 3.52 vs 75.91 ± 1.59, 78.25 ± 2.15; IL-6: 80.94 ± 3.26 vs 59.65 ± 1.39, 65.57 ± 4.04, all P < 0.01). Curcumin decreased the expression of NF-κB (2.73 ± 0.79, 4.22 ± 1.09 vs 7.92 ± 1.24, both P < 0.01) and degradation of IκBα more significantly than dexamethasone.
CONCLUSION: Curcumin has a positive effect in treating DSS-induced colitis in mice. The therapeutic effect of curcumin is superior to dexamethasone. Curcumin reduces colonic inflammation by decreasing the expression of NF-κB and modulating the release of cytokines.
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Bouguen G, Chevaux JB, Peyrin-Biroulet L. Recent advances in cytokines: therapeutic implications for inflammatory bowel diseases. World J Gastroenterol 2011; 17:547-56. [PMID: 21350703 PMCID: PMC3040326 DOI: 10.3748/wjg.v17.i5.547] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 03/22/2010] [Accepted: 03/29/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mesenchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becoming a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of cytokines involved in IBD and new therapeutic opportunities for these diseases.
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Whitley NT, Day MJ. Immunomodulatory drugs and their application to the management of canine immune-mediated disease. J Small Anim Pract 2011; 52:70-85. [DOI: 10.1111/j.1748-5827.2011.01024.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Kim KO, Jang BI. Emerging Drugs in the Treatment of Inflammatory Bowel Disease: Beyond Anti-TNF-α. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011; 58:235-44. [DOI: 10.4166/kjg.2011.58.5.235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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Danese S, Angelucci E. New and emerging biologics in the treatment of inflammatory bowel disease: quo vadis? ACTA ACUST UNITED AC 2010; 33 Suppl 3:S217-27. [PMID: 20117345 DOI: 10.1016/s0399-8320(09)73157-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel diseases (IBD) are pathological conditions characterized by chronic inflammation that is primarily the consequence of dysregulation of the immune response. Over the last decade, the advances in the pathophysiology of IBD have paved the way for the development of a number of biological agents that selectively target specific molecules and/or pathways involved in gut inflammation. Although numerous, so far, the only biological therapeutics that are approved for the treatment for IBD are monoclonal antibodies against tumor necrosis factor alpha. This paper systematically reviews the mechanismof-action, efficacy, short-term and, where available, long-term safety of biological agents that target molecules other than tumor necrosis factor alpha, in IBD.
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Affiliation(s)
- S Danese
- Division of Gastroenterology, Istituto Clinico Humanitas, IRCCS in Gastroenterology, Rozzano, Milan, Italy.
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Abstract
Curcumin is a natural product isolated from rhizome of Curcuma longa (turmeric). Extensive research over the past five decades has revealed several important functions of curcumin. Animal studies and clinical trials have suggested that curcumin has antioxidant, anti-inflammatory, anti-tumor and immunoregulatory effects. Ulcerative colitis (UC) is a chronic, idiopathic, relapsing intestinal inflammatory disorder of unknown etiology. In experimental colitis, curcumin mediates anti-inflammatory effects by modulating the release of cytokines, inhibiting nuclear factor-κB (NF-κB) and its upstream signaling pathway, activating peroxisome proliferator-activated receptor γ (PPARγ), and down-regulating the activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). At present, although there are studies suggesting that curcumin has therapeutic value for patients with UC, further studies are still needed to evaluate the clinical potential of curcumin in these patients.
Key Words: Curcumin; Ulcerative colitis; Cytokine; Nuclear factor-κB; Peroxisome proliferator-activated receptor γ; Cyclooxygenase-2; Inducible nitric oxide synthase
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Baumgart DC, Targan SR, Dignass AU, Mayer L, van Assche G, Hommes DW, Hanauer SB, Mahadevan U, Reinisch W, Plevy SE, Salzberg BA, Buchman AL, Mechkov GM, Krastev ZA, Lowder JN, Frankel MB, Sandborn WJ. Prospective randomized open-label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2010; 16:620-9. [PMID: 19714757 DOI: 10.1002/ibd.21084] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). METHODS In all, 104 patients were treated. In Stage I, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 microg/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 microg/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. RESULTS The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 70%, 50%, and 61%, respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 35%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. CONCLUSIONS Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 microg/kg/day were similar to those observed with higher doses.
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Affiliation(s)
- Daniel C Baumgart
- Department of Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School of the Humboldt-University of Berlin, Germany.
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Abstract
Gut inflammation occurring in patients with IBDs (inflammatory bowel diseases) is associated with exaggerated and poorly controlled T-cell-mediated immune responses, which are directed against normal components of the gut flora. T-cells accumulate in the inflamed gut of IBD patients as a result of multiple mechanisms, including enhanced recruitment of cells from the bloodstream, sustained cell cycling and diminished susceptibility of cells to undergo apoptosis. Activated T-cells produce huge amounts of cytokines, which contribute to amplify and sustain the ongoing mucosal inflammation. Strategies aimed at interfering with T-cell accumulation and/or function in the gut have been employed with clinical success in patients with IBDs. In the present article, we review the available results showing that T-cell-directed therapies are useful to dampen the tissue-damaging immune response in IBDs.
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Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 2010; 120:76-85. [PMID: 20188830 DOI: 10.1016/j.jsbmb.2010.02.018] [Citation(s) in RCA: 207] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 02/15/2010] [Accepted: 02/16/2010] [Indexed: 12/13/2022]
Abstract
Glucocorticoids are the most effective anti-inflammatory therapy for many chronic inflammatory and immune diseases, such as asthma, but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease (COPD). Glucocorticoids suppress inflammation by several mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors (GR) to coactivator molecules and recruitment of histone deacetylase-2 (HDAC2) to the activated transcription complex. At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with COPD and cystic fibrosis. Several molecular mechanisms of glucocorticoid resistance have now been identified. HDAC2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of glucocorticoids. Dissociated glucocorticoids have been developed to reduce side effects but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects. In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanism of glucocorticoid resistance.
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Pastorelli L, Pizarro TT, Cominelli F, Vecchi M. Emerging drugs for the treatment of ulcerative colitis. Expert Opin Emerg Drugs 2009; 14:505-21. [PMID: 19656075 DOI: 10.1517/14728210903146882] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colon for which the etiology is currently unknown. At present, strategies to treat UC are primarily targeted to control inflammation during active phases of disease as well as maintain remission during quiescence. As such, several unmet needs in the treatment of UC still remain. In recent years, basic research has led to the recognition of several key factors in the pathogenesis of UC, translating into the development of several novel therapeutic agents. OBJECTIVE The aim of this study is to review emerging therapies that may advance the treatment and improve the overall care of UC patients. METHODS An extensive literature search on published manuscripts and meeting proceedings has been performed to provide a comprehensive review of future drug therapies to treat UC. RESULTS/CONCLUSION The translational application of new discoveries in the basic understanding of UC pathogenesis is continuing and critical for the development of novel treatment strategies. Design of novel biologic therapies to treat UC has the challenge of addressing potential safety issues, while more traditional drugs should be further developed to facilitate patient compliance to treat this chronic, debilitating disease.
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Affiliation(s)
- Luca Pastorelli
- Case Western Reserve University School of Medicine, Department of Pathology, 2103 Cornell Road, Room 5501, Cleveland, OH, 44106, USA
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Yarkoni S, Sagiv Y, Kaminitz A, Farkas DL, Askenasy N. Targeted therapy to the IL-2R using diphtheria toxin and caspase-3 fusion proteins modulates Treg and ameliorates inflammatory colitis. Eur J Immunol 2009; 39:2850-64. [DOI: 10.1002/eji.200839190] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Abstract
Ulcerative colitis is a chronic relapsing and remitting inflammatory disorder that can generally be managed successfully with maintenance oral medications. However, approximately 15% of patients with ulcerative colitis will develop a severe exacerbation and require hospitalization. While many patients with acute severe ulcerative colitis will respond to a short course of intravenous corticosteroids, up to a third will fail to improve. In these patients with steroid-refractory colitis, the choice is between rescue medical therapy with ciclosporin or infliximab, or surgery. Well-timed rescue medical therapy is generally safe when administered by experienced physicians, and is effective in the majority of cases. Surgery is unavoidable in some cases, but is the treatment of choice in others. While ileal pouch-anal anastomosis offers the prospect of life without a permanent ileostomy, there are issues with its long-term functional outcome.
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Affiliation(s)
- Glen A Doherty
- Center for Inflammatory Bowel Disease, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
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Di Sabatino A, Rovedatti L, Kaur R, Spencer JP, Brown JT, Morisset VD, Biancheri P, Leakey NAB, Wilde JI, Scott L, Corazza GR, Lee K, Sengupta N, Knowles CH, Gunthorpe MJ, McLean PG, MacDonald TT, Kruidenier L. Targeting Gut T Cell Ca2+ Release-Activated Ca2+ Channels Inhibits T Cell Cytokine Production and T-Box Transcription Factor T-Bet in Inflammatory Bowel Disease. THE JOURNAL OF IMMUNOLOGY 2009; 183:3454-62. [DOI: 10.4049/jimmunol.0802887] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Creed TJ, Lee RW, Newcomb PV, di Mambro AJ, Raju M, Dayan CM. The Effects of Cytokines on Suppression of Lymphocyte Proliferation by Dexamethasone. THE JOURNAL OF IMMUNOLOGY 2009; 183:164-71. [DOI: 10.4049/jimmunol.0801998] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Abstract
Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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Affiliation(s)
- Peter J Barnes
- National Heart and Lung Institute, Imperial College, London, UK.
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Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology 2009; 136:1182-97. [PMID: 19249397 DOI: 10.1053/j.gastro.2009.02.001] [Citation(s) in RCA: 275] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Revised: 02/04/2009] [Accepted: 02/04/2009] [Indexed: 02/07/2023]
Abstract
Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti-tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin alpha4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully.
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Affiliation(s)
- Paul Rutgeerts
- Division of Gastroenterology, University of Leuven Hospitals, Leuven, Belgium.
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Moss AC, Peppercorn MA. Steroid-refractory severe ulcerative colitis: what are the available treatment options? Drugs 2008; 68:1157-67. [PMID: 18547130 DOI: 10.2165/00003495-200868090-00001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Approximately 15% of patients with ulcerative colitis will experience a severe episode requiring hospitalization. Although intravenous corticosteroids are the current first-line therapy for these patients, about 30% of patients do not respond to corticosteroids and require either an alternative anti-inflammatory agent or surgery. Ciclosporin has proven its efficacy in a number of controlled trials in this setting and is characterized by high early response rates. Patients who respond to ciclosporin and avoid colectomy are more likely to retain their colon if they bridge to immunomodulators in the medium term. Infliximab has also demonstrated efficacy in reducing early colectomy rates and longer term data are awaited. Other agents, such as tacrolimus and basiliximab, and leukocytapheresis, have been studied in small trials and may be alternative options. Key issues remain as to what should be first- and second-line therapies, when surgery should be undertaken, and the risk of switching between immunosuppressants in these critical patients.
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Affiliation(s)
- Alan C Moss
- Harvard Medical School, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
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Price M, Probert CSJ, Creed T. Basiliximab and infliximab for the treatment of steroid-refractory Crohn's disease. Am J Gastroenterol 2008; 103:2665. [PMID: 18855871 DOI: 10.1111/j.1572-0241.2008.02074_14.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Sanchez-Muñoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol 2008; 14:4280-8. [PMID: 18666314 PMCID: PMC2731177 DOI: 10.3748/wjg.14.4280] [Citation(s) in RCA: 506] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), represents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal macrophages play an important role in the mucosal immune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major contributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cytokine therapies have been developed and tested for the treatment of IBD patients.
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