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Haydinger CD, Ashander LM, Tan ACR, Smith JR. Intercellular Adhesion Molecule 1: More than a Leukocyte Adhesion Molecule. BIOLOGY 2023; 12:biology12050743. [PMID: 37237555 DOI: 10.3390/biology12050743] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/15/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023]
Abstract
Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein in the immunoglobulin superfamily expressed on the surface of multiple cell populations and upregulated by inflammatory stimuli. It mediates cellular adhesive interactions by binding to the β2 integrins macrophage antigen 1 and leukocyte function-associated antigen 1, as well as other ligands. It has important roles in the immune system, including in leukocyte adhesion to the endothelium and transendothelial migration, and at the immunological synapse formed between lymphocytes and antigen-presenting cells. ICAM-1 has also been implicated in the pathophysiology of diverse diseases from cardiovascular diseases to autoimmune disorders, certain infections, and cancer. In this review, we summarize the current understanding of the structure and regulation of the ICAM1 gene and the ICAM-1 protein. We discuss the roles of ICAM-1 in the normal immune system and a selection of diseases to highlight the breadth and often double-edged nature of its functions. Finally, we discuss current therapeutics and opportunities for advancements.
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Affiliation(s)
- Cameron D Haydinger
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia
| | - Liam M Ashander
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia
| | - Alwin Chun Rong Tan
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia
| | - Justine R Smith
- College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia
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Domazetovic V, Bonanomi AG, Stio M, Vincenzini MT, Iantomasi T. Resveratrol decreases TNFα-induced ICAM-1 expression and release by Sirt-1-independent mechanism in intestinal myofibroblasts. Exp Cell Res 2019; 382:111479. [DOI: 10.1016/j.yexcr.2019.06.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/17/2019] [Accepted: 06/20/2019] [Indexed: 02/07/2023]
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The role of adhesion molecules in inflammatory bowel disease in children. Assessment of the possible risk of cardiovascular complications. GASTROENTEROLOGY REVIEW 2017; 12:181-185. [PMID: 29123578 PMCID: PMC5672715 DOI: 10.5114/pg.2017.70480] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 08/17/2016] [Indexed: 11/17/2022]
Abstract
Introduction Inflammatory bowel diseases (IBD) are chronic diseases that proceed with exacerbation and remission phases. Adhesion molecules play a significant role in inflammatory processes. The same adhesion molecules play an important role in atherogenesis. Aim To assess the risk of atherosclerosis in IBD in children. Material and methods The study included 40 patients with IBD (25 with Crohn's disease - CD and 15 with ulcerative colitis - UC) aged 4-17 years. In the study group, concentrations of selected adhesion molecules (intracellular adhesion molecule - ICAM, vascular cell adhesion molecule - VCAM, E-selectin) and selected parameters of lipid metabolism in serum were assessed. Results No statistically significant differences between CD and UC patients and in the control group, in mean values of selected adhesins were obtained. Average variable VCAM was significantly lower in patients with CD than in patients with UC in the active stage of the diseases. Significantly higher average levels of triglycerides (TG) and high density lipoproteins (HDL) were found in the control group than in patients with CD. Significantly higher levels of total cholesterol (CHL) and HDL were noticed in the control group patients than in the patients with UC. The HDL/CHL was significantly higher in controls than in patients with UC. Conclusions No increased risk of developing atherosclerosis was found in children with IBD. Decreased risk in patients during exacerbation of inflammatory bowel disease was revealed, which may result from malnutrition typical for acute disease phase.
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Fontani F, Domazetovic V, Marcucci T, Vincenzini MT, Iantomasi T. Tumor Necrosis Factor-Alpha Up-Regulates ICAM-1 Expression and Release in Intestinal Myofibroblasts by Redox-Dependent and -Independent Mechanisms. J Cell Biochem 2015; 117:370-81. [DOI: 10.1002/jcb.25279] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/08/2015] [Indexed: 12/19/2022]
Affiliation(s)
- Filippo Fontani
- Department of Biomedical; Experimental and Clinical Sciences “Mario Serio”; University of Florence; Viale Morgagni 50; 50134 Florence; Italy
| | - Vladana Domazetovic
- Department of Biomedical; Experimental and Clinical Sciences “Mario Serio”; University of Florence; Viale Morgagni 50; 50134 Florence; Italy
| | - Tommaso Marcucci
- Santa Maria Annunziata Hospital; Section of General Surgery; 50126 Via dell'Antella 58, Ponte a Niccheri (Florence); Italy
| | - Maria Teresa Vincenzini
- Department of Biomedical; Experimental and Clinical Sciences “Mario Serio”; University of Florence; Viale Morgagni 50; 50134 Florence; Italy
| | - Teresa Iantomasi
- Department of Biomedical; Experimental and Clinical Sciences “Mario Serio”; University of Florence; Viale Morgagni 50; 50134 Florence; Italy
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Martinesi M, Ambrosini S, Treves C, Zuegel U, Steinmeyer A, Vito A, Milla M, Bonanomi AG, Stio M. Role of vitamin D derivatives in intestinal tissue of patients with inflammatory bowel diseases. J Crohns Colitis 2014; 8:1062-1071. [PMID: 24630484 DOI: 10.1016/j.crohns.2014.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 02/07/2014] [Accepted: 02/07/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM The adhesion molecule expression and matrix metalloproteinases (MMPs) are proposed to be major factors for intestinal injury mediated by T cells in (IBD) and are up-regulated in intestinal mucosa of IBD patients. To investigate the effect of vitamin D derivatives on adhesion molecules and MMPs in colonic biopsies of IBD patients. METHODS Biopsies from inflamed and non-inflamed tract of terminal ileum and colon and PBMC from the same IBD patients were cultured with or without vitamin D derivatives. MMP activity and adhesion molecule levels were determined. RESULTS 1,25(OH)2D3 and ZK 191784 significantly decrease ICAM-1 protein levels in the biopsies obtained only from the inflamed region of intestine of UC patients, while MAdCAM-1 levels decrease in the presence of 1,25(OH)2D3 in the non-inflamed region, and, in the presence of ZK, in the inflamed one. In CD patients 1,25(OH)2D3 and ZK decrease ICAM-1 and MAdCAM-1 in the biopsies obtained from the non-inflamed and inflamed regions, with the exception of ICAM-1 in the inflamed region in the presence of 1,25(OH)2D3. The expression of MMP-9, MMP-2, and MMP-3 decreases in the presence of vitamin D derivatives in UC and CD with the exception of 1,25(OH)2D3 that does not affect the levels of MMP-9 and MMP-2 in CD. Vitamin D derivatives always affect MMP-9, MMP-2 and ICAM-1 in PBMC of UC and CD patients. CONCLUSIONS Based on the increased expression of ICAM-1, MAdCAM-1 and MMP-2,-9,-3 in IBD, our study suggests that vitamin D derivatives may be effective in the management of these diseases.
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Affiliation(s)
- Maria Martinesi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Stefano Ambrosini
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Cristina Treves
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Ulrich Zuegel
- Clinical Sciences, Global Biomarker, Global Discovery, Bayer Healthcare, Bayer, 10178 Berlin, Germany
| | - Andreas Steinmeyer
- Medicinal Chemistry, Global Drug Discovery, Bayer Healthcare, Bayer, 10178 Berlin, Germany
| | - Annese Vito
- Division of Gastroenterology 2, Careggi Hospital, 50134 Florence, Italy
| | - Monica Milla
- Regional Referral Center for IBD, Careggi Hospital, 50134 Florence, Italy
| | - Andrea G Bonanomi
- Division of Gastroenterology 2, Careggi Hospital, 50134 Florence, Italy
| | - Maria Stio
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
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Laroui H, Viennois E, Xiao B, Canup BSB, Geem D, Denning TL, Merlin D. Fab'-bearing siRNA TNFα-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis. J Control Release 2014; 186:41-53. [PMID: 24810114 DOI: 10.1016/j.jconrel.2014.04.046] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 03/07/2014] [Accepted: 04/25/2014] [Indexed: 12/30/2022]
Abstract
Patients suffering from inflammatory bowel disease (IBD) are currently treated by systemic drugs that can have significant side effects. Thus, it would be highly desirable to target TNFα siRNA (a therapeutic molecule) to the inflamed tissue. Here, we demonstrate that TNFα siRNA can be efficiently loaded into nanoparticles (NPs) made of poly (lactic acid) poly (ethylene glycol) block copolymer (PLA-PEG), and that grafting of the Fab' portion of the F4/80 Ab (Fab'-bearing) onto the NP surface via maleimide/thiol group-mediated covalent bonding improves the macrophage (MP)-targeting kinetics of the NPs to RAW264.7 cells in vitro. Direct binding was shown between MPs and the Fab'-bearing NPs. Next, we orally administered hydrogel (chitosan/alginate)-encapsulated Fab'-bearing TNFα-siRNA-loaded NPs to 3% dextran sodium sulfate (DSS)-treated mice and investigated the therapeutic effect on colitis. In vivo, the release of TNFα-siRNA-loaded NPs into the mouse colon attenuated colitis more efficiently when the NPs were covered with Fab'-bearing, compared to uncovered NPs. All DSS-induced parameters of colonic inflammation (e.g., weight loss, myeloperoxidase activity, and Iκbα accumulation) were more attenuated Fab'-bearing NPs loaded with TNFα siRNA than without the Fab'-bearing. Grafting the Fab'-bearing onto the NPs improved the kinetics of endocytosis as well as the MP-targeting ability, as indicated by flow cytometry. Collectively, our results show that Fab'-bearing PLA-PEG NPs are powerful and efficient nanosized tools for delivering siRNAs into colonic macrophages.
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Affiliation(s)
- Hamed Laroui
- Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA.
| | - Emilie Viennois
- Institute for Biomedical Sciences, USA; Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA; Veterans Affair Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA
| | - Bo Xiao
- Institute for Biomedical Sciences, USA; Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA
| | - Brandon S B Canup
- Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA
| | - Duke Geem
- Institute for Biomedical Sciences, USA; Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA
| | - Timothy L Denning
- Institute for Biomedical Sciences, USA; Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, USA; Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA; Veterans Affair Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA
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Anti-inflammatory effect of elemental diets with different fat composition in experimental colitis. Br J Nutr 2013; 111:1213-20. [DOI: 10.1017/s0007114513003632] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The aim of the present study was to evaluate the effectiveness of two isoenergetic elemental formulae with different fat content in the rat model of trinitrobenzene sulphonic acid (TNBS) colitis that mimics human inflammatory bowel disease. A total of forty-five male Wistar rats were assigned to five groups: (1) control group; (2) TNBS-induced colitis group; (3) TNBS-induced colitis group fed a long-chain TAG (LCT)-rich diet; (4) TNBS-induced colitis group fed a medium-chain TAG (MCT)-rich diet; (5) TNBS-induced colitis group fed a baseline diet and administered infliximab. Nutritional management lasted 12 d before and 4 d after rectal administration of TNBS. Subsequently, the rats were killed, and colonic tissue samples were collected for the assessment of histology, inflammation and oxidative stress. The MCT-rich diet decreased IL-6, IL-8 and intercellular adhesion molecule-1 (ICAM-1) levels and glutathione S-transferase (GST) activity, while the LCT-rich diet reduced only ICAM-1 levels and GST activity (P< 0·05). Neither elemental formula affected IL-10 levels. Infliximab reduced IL-8 and ICAM-1 levels and GST activity and increased IL-10 levels (P< 0·05). No significant differences were detected in oxidative stress. Histological damage scores differed significantly only between the control and the TNBS-induced colitis group. A MCT-rich formula seems to exert stronger anti-inflammatory effects than a LCT-rich formula in TNBS colitis.
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Abdel-Aziz H, Wadie W, Abdallah DM, Lentzen G, Khayyal MT. Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2013; 20:585-591. [PMID: 23453305 DOI: 10.1016/j.phymed.2013.01.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 12/11/2012] [Accepted: 01/26/2013] [Indexed: 06/01/2023]
Abstract
Evidence suggests an important role of intestinal barrier dysfunction in the etiology of inflammatory bowel disease (IBD). Therefore stabilizing mucosal barrier function constitutes a new therapeutic approach in its management. Ectoine is a compatible solute produced by aerobic chemoheterotrophic and halophilic/halotolerant bacteria, where it acts as osmoprotectant and effective biomembrane stabilizer, protecting the producing cells from extreme environmental stress. Since this natural compound was also shown to prevent inflammatory responses associated with IBD, its potential usefulness was studied in a model of colitis. Groups of rats were treated orally with different doses of ectoine (30-300 mg/kg) or sulfasalazine (reference drug) daily for 11 days. On day 8 colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid, when overt signs of lesions develop within the next 3 days. On day 12, blood was withdrawn from the retro-orbital plexus of the rats and the animals were sacrificed. The colon was excised and examined macroscopically and microscopically. Relevant parameters of oxidative stress and inflammation were measured in serum and colon homogenates. Induction of colitis led to marked weight loss, significant histopathological changes of the colon, and variable changes in levels of myeloperoxidase, reduced glutathione, malondialdehyde, and all inflammatory markers tested. Treatment with ectoine ameliorated the inflammatory changes in TNBS-induced colitis. This effect was associated with reduction in the levels of TNF-α, IL-1β, ICAM-1, PGE2 and LTB4. The findings suggest that intestinal barrier stabilizers from natural sources could offer new therapeutic measures for the management of IBD.
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Vainer B. Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: presence, visualization, and significance. APMIS 2010:1-43. [PMID: 20653648 DOI: 10.1111/j.1600-0463.2010.02647.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Ben Vainer
- Department of Pathology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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10
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Gaddi E, Laucella S, Balbaryski J, Cantisano C, Barboni G, Candi M, Giraudi V. Prognostic Value of Soluble Intercellular Adhesion Molecule-1 (s-ICAM-1) in HIV-Infected Children. Scand J Immunol 2008. [DOI: 10.1111/j.1365-3083.2000.00820.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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11
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Torrence AE, Brabb T, Viney JL, Bielefeldt-Ohmann H, Treuting P, Seamons A, Drivdahl R, Zeng W, Maggio-Price L. Serum biomarkers in a mouse model of bacterial-induced inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:480-90. [PMID: 18095317 DOI: 10.1002/ibd.20347] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The diagnosis and classification of inflammatory bowel disease (IBD) require both clinical and histopathologic data. Serum biomarkers would be of considerable benefit to noninvasively monitor the progression of disease, assess effectiveness of therapies, and assist in understanding disease pathogenesis. Currently, there are limited noninvasive biomarkers for monitoring disease progression in animal IBD models, which are used extensively to develop new therapies and to understand IBD pathogenesis. METHODS Serum biomarkers of early and late IBD were identified using multianalyte profiling in mdr1a(-/-) mice with IBD triggered by infection with Helicobacter bilis. The correlation of changes in these biomarkers with histopathology scores and clinical signs in the presence and in the absence of antibiotic treatment was determined. RESULTS Serum levels of interleukin (IL)-11, IL-17, 10-kDa interferon-gamma-inducible protein (IP-10), lymphotactin, monocyte chemoattractant protein (MCP)-1, and vascular cell adhesion molecule (VCAM)-1 were elevated early in IBD. In late, more severe IBD, serum levels of IL-11, IP-10, haptoglobin, matrix metalloproteinase-9, macrophage inflammatory protein (MIP)-1gamma, fibrinogen, immunoglobulin A, MIP-3 beta (beta), VCAM-1, apolipoprotein (Apo) A1, and IL-18 were elevated. All late serum biomarkers except Apo A1 correlated with histopathology scores. Antibiotic treatment improved clinical signs of IBD and decreased mean serum values of many of the biomarkers. For all biomarkers, the individual pathology scores correlated significantly with individual serum analyte levels after treatment. CONCLUSIONS Serum analyte measurement is a useful, noninvasive method for monitoring disease in a mouse model of bacterial-induced IBD.
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Affiliation(s)
- Anne E Torrence
- Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.
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12
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Abstract
Both ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel diseases, are recognized, at the moment, as perplexing and challenging clinical entities, in which several molecules and cell types are implicated. Recent molecular evidence proposes the intestinal microvascular remodelling or angiogenesis, as a phenomenon implicated in the pathogenesis of these chronic inflammatory disorders, together with other proposed theories involved in the pathogenesis of inflammatory bowel diseases, such as genetic, microbacterial and immune factors. Intestinal damage is followed by a physiological angiogenesis, but the abnormal expression of pro- and anti-angiogenic molecules and the changes of vascular cell types could reflect a pathological vascular remodelling. Thus, the inflammation may be favoured and maintained by a pathological angiogenesis. A better understanding of the angiogenic process may facilitate the design of more effective therapies for chronic intestinal inflammation.
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Affiliation(s)
- I D Pousa
- Department of Gastroenterology and Ciberehd, University Hospital of La Princesa, Universidad Autónoma Madrid, Spain
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13
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Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease. J Gastroenterol 2007; 42:787-98. [PMID: 17940831 DOI: 10.1007/s00535-007-2096-y] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Accepted: 07/18/2007] [Indexed: 02/04/2023]
Abstract
Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in inflammatory bowel disease (IBD). Current advances have defined the mechanisms by which neutrophils are activated or migrate across endothelial and mucosal epithelial cells. A better understanding of this process will likely provide new insights into novel treatment strategies for IBD. Especially, activated neutrophils produce reactive oxygen and nitrogen species and myeloperoxidase within intestinal mucosa, which induce oxidative stress. Posttranslational modification of proteins generated by these reactive species serves as a "molecular fingerprint" of protein modification by lipid peroxidation-, nitric oxide-, and myeloperoxidase-derived oxidants. Measurement of these modified proteins may serve both as a quantitative index of oxidative stress and an important new biological marker of clinical relevance to IBD. We have succeeded in the clinical development of a novel granulocyte adsorptive apheresis therapy for IBD. In this review, we discuss current advances in defining the role of neutrophil-dependent oxidative stress in IBD.
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14
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Neuman MG. Immune dysfunction in inflammatory bowel disease. Transl Res 2007; 149:173-86. [PMID: 17383591 DOI: 10.1016/j.trsl.2006.11.009] [Citation(s) in RCA: 165] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2006] [Revised: 11/19/2006] [Accepted: 11/21/2006] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are idiopathic inflammatory bowel diseases (IBDs) that are characterized by chronic periods of exacerbation and remission. Research into the immunopathogenesis of IBD adds support to the theory that the disease results from a dysfunctional regulation of the immune system that leads to the polarization of intestinal immune cells toward a Th1 (T helper) response. The immunologic factors that mediate alterations in intestinal homeostasis and the development of intestinal mucosal inflammation have been at the forefront of IBD research. Cytokines, which are important regulators of leukocyte trafficking and apoptotic cell death, have emerged as essential immune molecules in the pathogenesis of IBD. In this study, recent advances in the understanding of the dynamism of cytokines and the consequences for mucosal immunity and inflammation in IBD are discussed. Furthermore, this study highlights the potential use of cytokines, anti-cytokine antibodies, and cytokine-related biologic therapies as novel targets for the treatment of IBD.
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Affiliation(s)
- Manuela G Neuman
- Department of Pharmacology and Institute of Drug Research, University of Toronto, Toronto, Ontario, Canada.
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Yadav V, Marracci G, Lovera J, Woodward W, Bogardus K, Marquardt W, Shinto L, Morris C, Bourdette D. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler 2005; 11:159-65. [PMID: 15794388 DOI: 10.1191/1352458505ms1143oa] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Lipoic acid (LA) is an antioxidant that suppresses and treats an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. The purpose of this study was to determine the pharmacokinetics (PK), tolerability and effects on matrix metalloproteinase-9 (MMP-9) and soluble intercellular adhesion molecule-1 (sICAMP-1) of oral LA in patients with MS. Thirty-seven MS subjects were randomly assigned to one of four groups: placebo, LA 600 mg twice a day, LA 1200 mg once a day and LA 1200 mg twice a day. Subjects took study capsules for 14 days. We found that subjects taking 1200 mg LA had substantially higher peak serum LA levels than those taking 600 mg and that peak levels varied considerably among subjects. We also found a significant negative correlation between peak serum LA levels and mean changes in serum MMP-9 levels (T = -0.263, P =0.04). There was a significant dose response relationship between LA and mean change in serum sICAM-1 levels (P =0.03). We conclude that oral LA is generally well tolerated and appears capable of reducing serum MMP-9 and sICAM-1 levels. LA may prove useful in treating MS by inhibiting MMP-9 activity and interfering with T-cell migration into the CNS.
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Affiliation(s)
- V Yadav
- Department of Veterans Affairs Medical Center, Portland, OR, USA
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Murthy S, Flanigan A, Osborne BJ, Murthy NS. Inflammatory bowel diseases: a new wave of therapy. Expert Opin Ther Pat 2005. [DOI: 10.1517/13543776.8.7.785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Rutgeerts P, Van Deventer S, Schreiber S. Review article: the expanding role of biological agents in the treatment of inflammatory bowel disease - focus on selective adhesion molecule inhibition. Aliment Pharmacol Ther 2003; 17:1435-50. [PMID: 12823145 DOI: 10.1046/j.1365-2036.2003.01603.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease presents in various forms. Its increasing incidence indicates that modern lifestyle triggers disease in genetically susceptible individuals. We present a model for inflammatory bowel disease pathophysiology and review the new biological therapies available. These biological agents have been developed to antagonise the processes of pathogenic inflammation, such as the reduction in T-lymphocyte apoptosis, increase in T-lymphocyte proliferation and increase in T-lymphocyte trafficking into the intestinal mucosa. Inhibitors of various inflammatory cytokines, including some antagonists to tumour necrosis factor, are effective therapies for inflammatory bowel disease. However, this class is associated with the risk of rare, but serious, side-effects, such as opportunistic infections and demyelinating diseases. The administration of anti-inflammatory cytokines, including interleukin-10 and interleukin-11, may theoretically be effective in reducing inflammation, although the clinical development of some of these therapies has been terminated. The selective inhibition of the adhesion molecules involved in T-lymphocyte trafficking can be effective in reducing gut inflammation. Of the selective adhesion molecule inhibitors under investigation, natalizumab has demonstrated efficacy in inflammatory bowel disease. The future of biological therapy for inflammatory bowel disease shows promise.
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Affiliation(s)
- P Rutgeerts
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
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Babic Z, Jagić V, Petrović Z, Bilić A, Dinko K, Kubat G, Troskot R, Vukelić M. Elevated serum values of procollagen III peptide (PIIIP)in patients with ulcerative colitis who will develop pseudopolyps. World J Gastroenterol 2003; 9:619-21. [PMID: 12632532 PMCID: PMC4621596 DOI: 10.3748/wjg.v9.i3.619] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the impact of procollagen III peptide as a marker of collagenesis in the development of pseudopolyps in patients with ulcerative colitis.
METHODS: Development of pseudopolyps was monitored in 25 patients with ulcerative colitis classified according to Powell-Tuck index as mild (n = 12) or moderate (n = 13) form of disease. Patients with a mild form of disease were treated with oral mesalazine medication (2-4 g/day) and local mesalazine preparation (suppository). Patients with a moderate form of disease received oral mesalazine medication (2-4 g/day), local mesalazine preparation (suppository) and local methylprednisolone at an initial dose of 60 mg/day, followed by dose tapering. How many significant variables (previously determined by analysis of variance) were elevated in the groups with and without pseudopolyp developement was observed. ROC analysis for calculation of new index was made.
RESULTS: Serum values of procollagen III peptide (PIIIP), C-reactive protein (CRP) and C4 complement component (C4) were statistically significantly lower in the group of patients free from pseudopolyp development than those who developed one or more pseudopolyps (0.45 ± 0.12 vs 1.42 ± 0.70, P < 0.0027; 7.6 ± 4.7 vs 17.8 ± 9.17, P < 0.035; and 0.46 ± 0.11 vs 0.34 ± 0.16, P < 0.068, respectively) at endoscopic conrtrols with patohistologically samples during 13 months. There were no statistically significant differences in the values of C3, ceruloplasmin and IgM between the two groups (P > 0.05). Discrimination function analysis yielded highest standardized cannon coefficients for PIIIP (0.876), CRP (0.104), C3 (-0.534) and C4 (0.184) (P < 0.036). The elevation in two of three laboratory variables (PIIIP, CRP and C4) reached sensitivity of 93% and specificity of 90% in the development of pseudopolyps.
CONCLUSION: It is proposed that an increase in two of the three laboratory parameters (PIIIP, CRP and C4) could improve the accuracy of prediction of the development of pseudopolyps. When using PIIIP, CRP and C4 on decision making, the positive predictive value and accuracy were 90% and 92%, respectively.
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Affiliation(s)
- Zarko Babic
- Division of Hepatogastroenterology, Department of Medicine, Sveti Duh General Hospital, Zagreb, Croatia.
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20
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Vainer B, Nielsen OH. Correlation between circulating soluble ICAM-1 and prednisolone-induced amelioration of ulcerative colitis. Scand J Gastroenterol 2003; 38:283-7. [PMID: 12737443 DOI: 10.1080/00365520310000609a] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND A soluble form of intercellular adhesion molecule-1 (sICAM-1) shed from endothelial cells is present in the circulation. Whether the circulating molecules represent passive turnover of surface ICAM-1 or may have some active functions in the inflammatory process is unknown. Glucocorticoids (e.g. prednisolone) are cornerstones in the treatment of acute exacerbations of ulcerative colitis (UC), and influence of the leucocyte/endothelial interaction appears to be part of their mode of action. The aim of the present study was therefore to evaluate the ICAM-1-shedding through measurements of sICAM-1 concentrations during prednisolone treatment of UC patients. METHODS Prednisolone (40 mg) was prescribed to 15 patients with severe disease activity. At inclusion, and after 2 weeks of treatment, plasma sICAM-1 levels were measured using the ELISA technique. RESULTS The concentrations of sICAM-1 were significantly decreased during treatment from median 256.2 (ng/ml) (interquartile range 239.7-321.0 ng/ml) to 220.4 ng/ml (196.0-276.3 ng/ml) (P < 0.01). This reduction correlated with a decrease in disease activity (r(s) = 0.8; P < 0.003). CONCLUSIONS sICAM-1 seems to be a poor diagnostic tool, but since plasma sICAM-1 concentrations decreased during the treatment period, it might prove to be applicable as an activity marker in the individual patient.
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Affiliation(s)
- B Vainer
- Dept. of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
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21
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Thomas PD, Forbes A, Price AB, Nicholls RJ, Ciclitira PJ. Differential expression of cell adhesion molecules within inflamed ileal pouch mucosa: relationship to recruited cell subtypes. Eur J Gastroenterol Hepatol 2002; 14:137-44. [PMID: 11981337 DOI: 10.1097/00042737-200202000-00007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Endothelial-bound cell adhesion molecules are important in recruiting inflammatory cells to the mucosa in inflammatory bowel disease (IBD). Little is known of the expression of these molecules in relation to the recruitment of particular cell subtypes in the early course of mucosal inflammation. We therefore studied the expression of several adhesion molecules to examine their potential correlation with the cellular infiltrate in the inflamed ileal pouch, a possible disease model for ulcerative colitis. METHODS Eleven patients (group 1) with familial adenomatous polyposis (FAP) with no evidence of ileal pouch inflammation and 14 patients (group 2) with ileal pouch inflammation (all with a prior diagnosis of ulcerative colitis) underwent pouch endoscopy with biopsy. Cryostat sections of biopsies were immunostained using a three-stage immunoperoxidase method for the adhesion molecules intercellular adhesion molecule (ICAM-1), vascular cellular adhesion molecule (VCAM-1), E-selectin and mucosal addressin cell adhesion molecule 1 (MAdCAM-1). These results were correlated with immunostaining for the cell markers CD3, CD4, CD8, CD45RO, CD14 and CD15, which were quantified by computer image analysis. RESULTS MAdCAM-1, ICAM-1 and VCAM-1 were expressed to similar degrees on the endothelia of groups 1 and 2. In contrast, E-selectin was significantly increased in group 2 (P = 0.003) and correlated with immunostaining for CD15 (r = 0.72), CD4 (r = 0.55) and CD14 (r = 0.53). MAdCAM-1 expression did not correlate with any cell subset. CD15 was the only cell marker to be altered significantly, being increased in group 2 (P = 0.002). CONCLUSIONS The inflammatory process seen in ileal pouch inflammation is characterized by up-regulation of E-selectin and recruitment of CD15-positive cells, emphasizing the role of neutrophil recruitment and migration to the epithelium in the pathogenesis of this condition.
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Affiliation(s)
- P D Thomas
- Department of Gastroenterology, St Mark's Hospital, Harrow, UK
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22
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Farkas S, Herfarth H, Rössle M, Schroeder J, Steinbauer M, Guba M, Beham A, Schölmerich J, Jauch KW, Anthuber M. Quantification of mucosal leucocyte endothelial cell interaction by in vivo fluorescence microscopy in experimental colitis in mice. Clin Exp Immunol 2001; 126:250-8. [PMID: 11703368 PMCID: PMC1906186 DOI: 10.1046/j.1365-2249.2001.01544.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2001] [Indexed: 12/17/2022] Open
Abstract
Leucocyte recruitment to sites of intestinal inflammation is a crucial, multi-step process that leads ultimately to the accumulation of cells in the inflamed tissue. We established a new in vivo model system of experimental colitis to quantify leucocyte-endothelial cell interaction and leucocyte extravasation in the inflamed mucosa of the colon. Furthermore, we investigated the pathophysiological role of ICAM-1 in the intestinal microcirculation in vivo. Using the model of dextran sodium sulphate (DSS)-induced acute and chronic colitis in mice, in vivo microscopy was performed in the colonic submucosal postcapillary venules and the submucosal collecting venules in normal or inflamed murine colonic segments. ICAM-1 expression was blocked by an anti-ICAM-1 monoclonal antibody or by suppressing NF-kappaB activation by gliotoxin. Significant increases in leucocyte adhesiveness (51-fold in postcapillary venules, 30-fold in collecting venules, P < 0.01) and extravasation (6.5-fold) could be demonstrated as early as day 2 of DSS-application in acute colitis (P < 0.01). This was paralleled by increases in both the histological damage scores and myeloperoxidase activities. In chronic dextran sodium sulphate-induced colitis significant increases in leucocyte-endothelium interactions and leucocyte extravasation were observed. Blocking ICAM-1 expression with a monoclonal antibody or gliotoxin, leucocyte sticking and extravasation were significantly down-regulated in vivo compared to controls (> 70%; P < 0.01). This new model system offers the possibility to specifically assess the role of adhesion molecules in the colonic mucosa in vivo as well as to investigate and quantify the effectiveness of experimental therapeutic approaches in acute or chronic intestinal inflammation.
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Affiliation(s)
- S Farkas
- Department of Surgery, Klinik und Poliklinik für Chirurgie, Klinikum der Universität Regensburg, Regensburg, Germany.
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Abstract
The last decade has seen tremendous advances in our knowledge, which has led to genuine improvements in our understanding of the pathogenesis and management of inflammatory bowel disease (IBD). The combined power of cellular and molecular biology has begun to unveil the enigmas of IBD, and, consequently, substantial gains have been made in the treatment of IBD. Refinements in drug formulation have provided the ability to target distinct sites of delivery, while enhancing the safety and efficacy of older agents. Simultaneous progress in biotechnology has fostered the development of new agents that strategically target pivotal processes in disease pathogenesis. This article addresses our current understanding of the pathogenesis of IBD, including the latest developments in animal models and covers agents currently used in the treatment of IBD as well as emerging therapies.
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Affiliation(s)
- R J Farrell
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
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Gaddi E, Laucella S, Balbaryski J, Cantisano C, Barboni G, Candi M, Giraudi V. Prognostic value of soluble intercellular adhesion molecule-1 (s-ICAM-1) in HIV-infected children. Scand J Immunol 2000; 52:628-33. [PMID: 11119270 DOI: 10.1046/j.1365-3083.2000.00820.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Central events in the host defence system and immune-mediated damage are tightly regulated by cell adhesion molecules. Sera from 28 human immunodeficiency virus (HIV)-1 infected children divided into groups according to disease severity, six seroreverting (SR) children and 25 healthy controls were studied to detect the presence of soluble intercellular adhesion molecule-1 (s-ICAM-1). Soluble ICAM-1 levels were found to be significantly increased in HIV-infected children in comparison with SR children or healthy controls. Levels of soluble ICAM-1 were higher in patients with severe forms of HIV-infection than in those with a milder form of the disease. Significant differences in titers of s-ICAM-1 were recorded between SR children and HIV-infected children with mild disease or healthy controls. There was a significant correlation between s-ICAM-1 levels and the concentrations of beta 2 microglobulin (beta 2m) and, to a lesser extend, immunoglobulin A levels (IgA). Soluble ICAM-1 levels didn't change considerably in HIV-infected children in stable clinical conditions, independently of their clinical stage of the disease, during a follow-up period of 9-12 months. Conversely, s-ICAM-1 levels increased simultaneously with the appearance of new well-defined clinical disorders or decreased during the improvement of clinical conditions. A significant negative correlation was recorded between the titers of the s-ICAM-1 and the CD4(+) T-cell levels. These results suggest that the s-ICAM-1 might be another useful tool to evaluate disease progression.
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Affiliation(s)
- E Gaddi
- División Inmunología, Hospital Dr Pedro de Elizalde, Buenos Aires, Argentina.
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Vainer B, Nielsen OH, Hendel J, Horn T, Kirman I. Colonic expression and synthesis of interleukin 13 and interleukin 15 in inflammatory bowel disease. Cytokine 2000; 12:1531-6. [PMID: 11023669 DOI: 10.1006/cyto.2000.0744] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED A dysregulated local immune reaction with unbalanced cytokine expression seems essential in inflammatory bowel disease (IBD), i.e. ulcerative colitis (UC) and Crohn's disease (CD). Since the roles of interleukin (IL-)13 and IL-15 remain unclear, this study aimed at studying intestinal expression of IL-13 and IL-15 in IBD. METHODS In colonic biopsies from 24 UC, 18 CD, and 12 controls IL-13 and IL-15 were measured using ELISA, and their gene expressions were assessed by RT-PCR. Leukocytes were visualised histochemically. RESULTS Concentrations of IL-13 were decreased in UC (median 56 pg/mg tissue; interquartile range 30-99 pg/mg) compared to CD (82 pg/mg tissue; 41-122;P=0.004) and controls (83 pg/mg tissue; 18-134;P>0.05), and lower in active UC (53 pg/mg tissue; 33-96) than in inactive UC (80 pg/mg tissue; 65-99;P=0.02). IL-15 concentrations were higher in CD patients (34 pg/mg tissue; 24-53) as compared to controls (20 pg/mg tissue; 15-21;P=0.001) whilst being 22 pg/mg tissue (15-32) in UC. IL-13 mRNA and IL-15 mRNA were detected in 20% and 15%, respectively. Infiltration of leukocytes correlated inversely with IL-13 levels (P=0.02). CONCLUSION Active UC is associated with decreased colonic IL-13 suggesting that IL-13 levels are diminished as a part of UC exacerbations, or that exacerbations follow active downregulation of IL-13.
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Affiliation(s)
- B Vainer
- Department of Medicine M, Division of Gastroenterology, Glostrup Hospital, University of Copenhagen, Denmark.
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Vainer B, Nielsen OH. Chemotactic properties of ICAM-1 and PECAM-1 on neutrophil granulocytes in ulcerative colitis: effects of prednisolone and mesalazine. Aliment Pharmacol Ther 2000; 14:1023-31. [PMID: 10930896 DOI: 10.1046/j.1365-2036.2000.00797.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND ICAM-1 seems to exhibit effects other than passive leucocyte/endothelial interaction. AIM To investigate the attracting properties of selected adhesion molecules, assessing the influence of the two major anti-inflammatory drugs in ulcerative colitis, prednisolone and mesalazine. METHODS Circulating neutrophils (11 ulcerative colitis, 15 controls) were assessed in microchemotaxis chambers by the leading front technique, using physiologically relevant concentrations of ICAM-1 (0.005-5000 pM), PECAM-1 (0.001-1000 nM), and P-selectin (0.01-100 nM). Neutrophils pre-incubated with prednisolone (10(-8)-10(-4) M) or mesalazine (0.65-10. 4 nM) were assessed towards ICAM-1. RESULTS Migration of neutrophils towards ICAM-1 showed a bell-shaped curve with a maximum at 5 pM (migration: 37.7 microm; P<0.001), whereas PECAM-1 attracted neutrophils equally in the range of 0.1-10 nM (25.0 microm; P<0.001). P-selectin had no cell-attracting effect. No differences were detected between cells from ulcerative colitis patients and controls. Pre-treatment with prednisolone decreased the cell attracting effect of ICAM-1 in a dose-dependent manner to 72% of the basal migration (P<0.001). Conversely, prednisolone showed a pro-chemokinetic effect by increasing the spontaneous locomotion of neutrophils by 40% (P<0.001). CONCLUSIONS Specific chemotactic properties were observed for ICAM-1 and PECAM-1. Prednisolone exhibited a dual effect in inhibiting the ICAM-1-mediated migration and stimulating the general locomotion of neutrophils.
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Affiliation(s)
- B Vainer
- Department of Medicine M, Division of Gastroenterology, Glostrup Hospital, University of Copenhagen, Denmark.
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Vainer B, Nielsen OH. Changed colonic profile of P-selectin, platelet-endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and ICAM-3 in inflammatory bowel disease. Clin Exp Immunol 2000; 121:242-7. [PMID: 10931137 PMCID: PMC1905699 DOI: 10.1046/j.1365-2249.2000.01296.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cell adhesion molecules (CAM) are essential for the capture and migration of leucocytes. Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by a continuous infiltration of leucocytes into intestinal tissue, and the colonic contents of P-selectin, PECAM-1, ICAM-1, ICAM-2, and ICAM-3 were therefore studied. Concentrations of these cell adhesion molecules were measured by an ELISA technique in sonicated colonic tissue from patients with UC and CD and controls with non-inflammatory disease and compared with the diagnosis and disease activity. P-selectin, PECAM-1, and ICAM-1 concentrations were elevated in UC patients compared with controls (P = 0.034, P = 0.014, P = 0.017, respectively), whereas that of ICAM-2 was not. The concentrations of these CAM did not differ in CD. In contrast, higher concentrations of ICAM-3 were found in the CD patients than in either UC (P = 0.001) or controls (P = 0.004). The CAM concentrations increased with disease activity, although only ICAM-1 was significantly elevated (P = 0.017). As considerable differences were found between UC and CD with comparable stages of inflammation, the mere presence of inflammation cannot solely explain the results. The observed differences in the CAM concentrations in UC and CD support the hypothesis that UC and CD are two distinct disease entities with separate pathogenic mechanisms.
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Affiliation(s)
- B Vainer
- Department of Medicine M, Division of Gastroenterology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
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Nielsen OH, Vainer B, Madsen SM, Seidelin JB, Heegaard NH. Established and emerging biological activity markers of inflammatory bowel disease. Am J Gastroenterol 2000; 95:359-67. [PMID: 10685736 DOI: 10.1111/j.1572-0241.2000.t01-1-01790.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion molecules. It is concluded that none of the pertinent laboratory surrogate markers of disease activity in IBD are specific or sensitive enough to replace basic clinical observation such as the number of daily bowel movements, general well-being, and other parameters in parallel. Further studies are highly warranted to identify and assess the clinical importance and applicability of new laboratory markers for the diagnosis or the disease activity of IBD.
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Affiliation(s)
- O H Nielsen
- Department of Medicine CF, Glostrup Hospital, University of Copenhagen, Denmark
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Bendjelloul F, Malý P, Mandys V, Jirkovská M, Prokesová L, Tucková L, Tlaskalová-Hogenová H. Intercellular adhesion molecule-1 (ICAM-1) deficiency protects mice against severe forms of experimentally induced colitis. Clin Exp Immunol 2000; 119:57-63. [PMID: 10606964 PMCID: PMC1905542 DOI: 10.1046/j.1365-2249.2000.01090.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
ICAM-1 (CD54), the ligand for LFA-1 and Mac-1, is up-regulated during inflammatory reaction on the activated vascular endothelium. To determine its role in intestinal inflammation, we induced acute experimental colitis in mice with a deleted ICAM-1 gene, by feeding them with 3% dextran sodium sulphate (DSS) in drinking water for 7 days. Chronic colitis was elicited by DSS similarly, followed by 2 weeks with water. In the acute phase of inflammation, ICAM-1-deficient mice exhibited a significantly lower mortality rate (5%) than control C57Bl/6J mice (35%). Control animals, but not the ICAM-1-deficient mice, exhibited diarrhoea and rectal bleeding. Histological examination of large-bowel samples evaluated the intensity of inflammatory changes, and type and extent of mucosal lesions. In the acute phase, 33.3% of samples from ICAM-1-deficient mice exhibited mucosal defects (flat and fissural ulcers), predominantly mild to moderate inflammatory infiltrate within the lamina propria mucosae and lower grades of mucosal lesions. Much stronger inflammatory changes were present in control animals, flat ulcers (sometimes multiple) and fissural ulcers being observed in 62.5% of samples. Mucosal inflammatory infiltrate was moderate to severe, typically with higher grades of mucosal lesions. In chronic colitis, smaller inflammatory changes were found in the large bowel. The two mouse strains differed, the chronic colitis being accompanied by an increased serum level of anti-epithelial IgA autoantibodies in C57Bl/6 control mice but not in ICAM-1-deficient mice. These findings provide direct evidence of the participation of ICAM-1 molecule in the development of experimentally induced intestinal inflammation.
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Affiliation(s)
- F Bendjelloul
- Division of Immunology and Gnotobiology, Institute of Microbiology, Charles University, Institute of Experimental Medicine, ASCR, Prague, Czech Republic
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Lazaris AC, Dicoglou C, Tseleni-Balafouta S, Paraskevakou H, Davaris PS. In situ expression of E-selectin and intercellular adhesion molecule-1 in chronic inflammatory diseases of the gastrointestinal tract. APMIS 1999; 107:819-27. [PMID: 10519316 DOI: 10.1111/j.1699-0463.1999.tb01477.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM The study of cell adhesion molecules contributes to our understanding of the inflammatory mechanisms which include the endothelial activation of newly formed or pre-existing vessels, the increase of inflammatory cells' adhesive capability and their migration into perivascular tissues. The aim of the present study was to investigate the local presence and the extent of expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in the mucosa of patients with chronic gastritis, chronic inflammatory bowel disease, and controls, as well as to identify possible correlations between in situ expression of the above adhesion molecules and degree of inflammatory activity or therapeutic response. DESIGN In cryostat tissue sections we examined the immunohistochemical expression and localization of E-selectin and the intercellular adhesion molecule-1 (ICAM-1). Our specimens consisted of 27 cases of chronic gastritis, 42 cases of ulcerative colitis, and 15 cases of Crohn's disease. RESULTS E-selectin was expressed in capillary endothelia as well as on neutrophils, located either in the lamina propria or in the glandular epithelia or lumina. This marker's expression was associated with the active phase of ulcerative colitis (p<0.0005) and possibly of chronic gastritis (p=0.06). ICAM-1 immunolabelling was localized in endothelia and chronic inflammatory components which had passed through the vascular walls. This marker's immunoreactivity was generally increased in all our specimens compared to normal mucosa and generally tended to correlate with chronic phases of the inflammatory process (p<0.10). CONCLUSIONS E-selectin regulates the accumulation of neutrophils in the early stages of the inflammatory process and is thus associated at least with the active phase of ulcerative colitis. Whether any post-therapy alteration of E-selectin immunopositivity seems to indicate a good response to drug therapy is well worth investigating in ulcerative colitis patients. ICAM-1 immunoreactivity in lymphoplasmacytic infiltrates might serve as a marker of chronic immune stimulation, which is potentially responsible for the persistence of the inflammatory disorders.
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Affiliation(s)
- A C Lazaris
- Department of Pathology, Athens National University Medical School, Greece
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31
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Lúdvíksson BR, Strober W, Nishikomori R, Hasan SK, Ehrhardt RO. Administration of mAb Against αEβ7 Prevents and Ameliorates Immunization-Induced Colitis in IL-2−/− Mice. THE JOURNAL OF IMMUNOLOGY 1999. [DOI: 10.4049/jimmunol.162.8.4975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Abstract
We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2−/− mouse that is caused by IL-12-driven CD4+ Th1 T cells and resembles human Crohn’s disease. The integrin αEβ7 is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of αEβ7 in colitis, we administered a mAb against αEβ7 to IL-2−/− mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0–2 vs 3–4, that was associated with a significant reduction in CD4+ lamina propria lymphocyte subpopulation (p < 0.01). In contrast, the total number of splenic CD4+ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 ± 0.6 × 107 vs 1.2 ± 0.2 × 107; p < 0.05). Similarly, functional studies revealed that IFN-γ production by lamina propria lymphocytes isolated from IL-2−/− TNP-OVA-immunized mice treated with anti-αEβ7 was significantly lower than in untreated IL-2−/− TNP-OVA-immunized mice. In contrast, IFN-γ production by splenic cells isolated from treated IL-2−/− TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2−/− mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after αEβ7 mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4+ lymphocytes expressing αEβ7.
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Affiliation(s)
- Björn R. Lúdvíksson
- *Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, and
| | - Warren Strober
- *Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, and
| | - Ryuta Nishikomori
- *Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, and
| | - Syed K. Hasan
- *Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, and
| | - Rolf O. Ehrhardt
- *Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, and
- †Protein Design Laboratories, Inc., Mountain View, CA 94043
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Conlong P, Nicholson DA, Shaffer JL, Jewell D. Crohn's Disease - Current views on Aetiology and its Impact on Management. J R Coll Physicians Edinb 1998. [DOI: 10.1177/147827159802800417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- P. Conlong
- North Manchester General Hospital, Crumpsall
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Poritz LS, Page MJ, Tilberg AF, Koltun WA. Amelioration of graft versus host disease with anti-ICAM-1 therapy. J Surg Res 1998; 80:280-6. [PMID: 9878325 DOI: 10.1006/jsre.1998.5422] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have previously demonstrated an increase in the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) in GVHD after small bowel transplantation (SBTx) and a therapeutic effect for the monoclonal antibody (MoAb) to LFA-1 in the same model. The present study evaluated the role of MoAb to LFA-1's ligand, intercellular adhesion molecule-1 (ICAM-1) in GVHD. Methods. GVHD was created in LBNF1 rats by heterotopic vascularized SBTx from Lewis donors. Saline treated SBTx-GVHD and sham-operated control animals were compared to animal groups treated with MoAb to ICAM-1 or MoAb to ICAM-1 and LFA-1. GVHD was evaluated by measuring spleen index, white blood cell count, bowel permeability, weight loss, and animal survival. RESULTS. Animals treated with the MoAb to ICAM-1 appeared clinically to have almost as severe GVHD as untreated animals; however, they had improved spleen indices, less neutropenia and weight loss, and survived longer than untreated animals (range 15-22 days in treated animals vs 12-16 days in untreated animals, P < 0. 01). Treatment with MoAb to both ICAM-1 and LFA-1 appeared to have a synergistic beneficial effect on GVHD (range 19-29 days, P < 0.001 vs untreated animals). Conclusion. MoAb to ICAM-1 alone or in combination with MoAb to LFA-1 ameliorates GHVD after SBTx and prolongs survival.
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Affiliation(s)
- L S Poritz
- Department of Sugery, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, 17033-0850, USA
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Schmal H, Czermak BJ, Lentsch AB, Bless NM, Beck-Schimmer B, Friedl HP, Ward PA. Soluble ICAM-1 Activates Lung Macrophages and Enhances Lung Injury. THE JOURNAL OF IMMUNOLOGY 1998. [DOI: 10.4049/jimmunol.161.7.3685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Abstract
Because of the important role of rat ICAM-1 in the development of lung inflammatory injury, soluble recombinant rat ICAM-1 (sICAM-1) was expressed in bacteria, and its biologic activities were evaluated. Purified sICAM-1 did bind to rat alveolar macrophages in a dose-dependent manner and induced production of TNF-α and the CXC chemokine, macrophage inflammatory protein-2 (MIP-2). Alveolar macrophages exhibited cytokine responses to both sICAM-1 and immobilized sICAM-1, while rat PBMCs failed to demonstrate similar responses. Exposure of alveolar macrophages to sICAM-1 resulted in NFκB activation (which was blocked by the presence of the aldehyde peptide inhibitor of 28S proteosome and by genistein, a tyrosine kinase inhibitor). As expected, cross-linking of CD18 on macrophages with Ab resulted in generation of TNF-α and MIP-2. This response was also inhibited in the presence of the proteosome inhibitor and by genistein. Alveolar macrophages showed adherence to immobilized sICAM-1 in a CD18-dependent manner. Finally, airway instillation of sICAM-1 intensified lung injury produced by intrapulmonary deposition of IgG immune complexes in a manner associated with enhanced lung production of TNF-α and MIP-2 and increased neutrophil recruitment. Therefore, through engagement of β2 integrins, sICAM-1 enhances alveolar macrophage production of MIP-2 and TNF-α, the result of which is intensified lung injury after intrapulmonary disposition of immune complexes.
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Affiliation(s)
- Hagen Schmal
- *Department of Traumatology, University of Freiburg, Freiburg, Germany
| | - Boris J. Czermak
- *Department of Traumatology, University of Freiburg, Freiburg, Germany
| | - Alex B. Lentsch
- ‡Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Nicolas M. Bless
- *Department of Traumatology, University of Freiburg, Freiburg, Germany
| | | | - Hans P. Friedl
- *Department of Traumatology, University of Freiburg, Freiburg, Germany
| | - Peter A. Ward
- ‡Department of Pathology, University of Michigan, Ann Arbor, MI 48109
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Kurkijärvi R, Adams DH, Leino R, Möttönen T, Jalkanen S, Salmi M. Circulating Form of Human Vascular Adhesion Protein-1 (VAP-1): Increased Serum Levels in Inflammatory Liver Diseases. THE JOURNAL OF IMMUNOLOGY 1998. [DOI: 10.4049/jimmunol.161.3.1549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Abstract
Vascular adhesion protein-1 (VAP-1) is a dimeric 170-kDa endothelial transmembrane molecule that under normal conditions is most strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. It is a glycoprotein that mediates tissue-selective lymphocyte adhesion in a sialic acid-dependent manner. In this study, we report the detection of a soluble form of VAP-1 in circulation. We developed a quantitative sandwich ELISA using novel anti-VAP-1 mAbs and used it to determine the levels of soluble VAP-1 (sVAP-1) in the serum of healthy individuals and in patients with inflammatory diseases. In healthy persons, circulating sVAP-1 concentrations were 49 to 138 ng/ml. Immunoblotting studies revealed that the apparent molecular mass of dimeric sVAP-1 is slightly (∼10 kDa) higher than that of transmembrane VAP-1 under nonreducing conditions. In contrast, the electrophoretic mobilities of monomeric sVAP-1 and transmembrane VAP-1 were similar after reduction and boiling. Adhesion assays showed that the circulating sVAP-1 modulates lymphocyte binding to endothelial cells. Inflammation can cause an elevation of serum sVAP-1 levels, because sVAP-1 concentrations in patients with certain liver diseases were two- to fourfold higher than those in normal individuals. In contrast, rheumatoid arthritis and inflammatory bowel diseases were not associated with elevated levels of sVAP-1. These findings indicate that there is a functionally active, soluble form of VAP-1 in circulation and suggest that the serum level of sVAP-1 might be a useful marker of disease activity in inflammatory liver diseases.
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Affiliation(s)
- Riikka Kurkijärvi
- *National Public Health Institute and MediCity Research Laboratory, Turku University, Turku, Finland
| | - David H. Adams
- †Liver Research Laboratories, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom; and
| | - Rauli Leino
- ‡Department of Internal Medicine, Turku University Central Hospital, Turku, Finland
| | - Timo Möttönen
- ‡Department of Internal Medicine, Turku University Central Hospital, Turku, Finland
| | - Sirpa Jalkanen
- *National Public Health Institute and MediCity Research Laboratory, Turku University, Turku, Finland
| | - Marko Salmi
- *National Public Health Institute and MediCity Research Laboratory, Turku University, Turku, Finland
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Affiliation(s)
- C Fiocchi
- Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Ohio, USA
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Breider MA, Eppinger M, Gough A. Intercellular adhesion molecule-1 expression in dextran sodium sulfate-induced colitis in rats. Vet Pathol 1997; 34:598-604. [PMID: 9396141 DOI: 10.1177/030098589703400608] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Orally administered dextran sodium sulfate (DSS) produces an acute colitis in rodents. The pathogenesis is unknown but may relate to DSS-mediated toxicity of colonic crypt epithelium and/or DSS-induced inflammation. The purpose of this study was to determine when colonic mucosal inflammation, as indicated by histopathology and intercellular adhesion molecule-1 (ICAM-1) expression, occurs relative to crypt epithelial damage. Groups of eight adult male Wistar rats were administered 5.0% DSS solution in the drinking water for 2-6 days. Clinical signs at 3 days consisted of loose stool, progressing to marked rectal hemorrhage by days 5 and 6 that correlated with marked intraluminal colonic hemorrhage at necropsy. Histological lesions of predominantly the distal colon consisted of multifocal areas of mucosal erosion, reduction in goblet cells, dilated crypts, crypt collapse, increased lamina propria neutrophils, and submucosal edema on days 2 and 3, progressing to locally extensive ulceration and marked mixed inflammatory infiltrates by days 4-6. Enhanced expression of ICAM-1, demonstrated by both immunohistochemical and northern blot analysis, was evident in colonic mucosa as early as day 2, with consistent increases through days 3-6. Results demonstrate that enhanced colonic mucosal endothelial cell ICAM-1 expression is an early event in the inflammatory cascade of DSS-induced colitis.
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Affiliation(s)
- M A Breider
- Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, MI, USA.
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Göke M, Hoffmann JC, Evers J, Krüger H, Manns MP. Elevated serum concentrations of soluble selectin and immunoglobulin type adhesion molecules in patients with inflammatory bowel disease. J Gastroenterol 1997; 32:480-6. [PMID: 9250894 DOI: 10.1007/bf02934086] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Adhesion molecules mediate the extravasation of leukocytes and their accumulation in inflamed tissues. In the present study, serum concentrations of the selectin (sP- and sE-selectin) and immunoglobulin supergene family (sICAM-1 and sVCAM-1) of adhesion molecules were measured in 93 patients with inflammatory bowel disease (Crohn's disease, n = 65; ulcerative colitis, n = 28) and 58 age-matched normal controls. sP-selectin serum concentrations (mean +/- SEM ng/ml) of patients with Crohn's disease (399 +/- 33 ng/ml) and ulcerative colitis (385 +/- 42 ng/ml) were increased (P = 0.0067 and P = 0.0193, respectively) compared to controls (251 +/- 33 ng/ml). In contrast, E-selectin serum levels of patients with Crohn's disease (58 +/- 5 ng/ml) and ulcerative colitis (64 +/- 12 ng/ml) were not significantly higher than those of controls (53 +/- 5 ng/ml). sICAM-1 serum concentrations of patients with Crohn's disease (420 +/- 19 ng/ml) and those with ulcerative colitis (375 +/- 40 ng/ml) were elevated (P = 0.0001 and P = 0.0473, respectively) compared to controls (297 +/- 8 ng/ml). Further, sVCAM-1 levels of patients with Crohn's disease (664 +/- 43 ng/ml) and ulcerative colitis (963 +/- 162 ng/ml) were increased (P = 0.0222 and P = 0.0121, respectively) compared to controls (510 +/- 31 ng/ml). With few exceptions, serum levels of soluble adhesion molecules were not significantly correlated to disease activity indices or disease localization. Elevated circulating selectin and immunoglobulin supergene type adhesion molecules may compete with membrane-bound forms for their cognate ligands and thereby limit the rolling and stable adhesion of leukocytes.
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Affiliation(s)
- M Göke
- Department of Gastroenterology and Hepatology, Medzinische Hochschule Hannover, Germany
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Abstract
Infiltration of leukocytes into the bowel wall is a landmark of the inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD). The leukocyte movement is dependent on physical contact (adhesion) between the leukocytes and activated endothelial cells and can be divided into capturing, rolling, leukocyte flattening, and extra-vasation. The molecules shown to form the basis of leukocyte-endothelial binding are referred to as cell adhesion molecules (CAMs). Several of these molecules have additional properties, including interaction between leukocytes and proteins in the extracellular matrix, collaen in basement membranes, and stromal cells in lymphoid tissue and bone marrow. Furthermore, studies have indicated that CAMs interfere with the tumor cell's ability to metastasize. This paper will focus on a description of those CAMs that are either known or believed to be involved in the pathogenesis of IBD. Investigations of the presence and functions of these CAMs in IBD is reviewed, and potential new treatments are discussed.
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Affiliation(s)
- B Vainer
- Dept. of Gastroenterology F Glostrup Hospital, University of Copenhagen, Denmark
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Abstract
CD11/CD18 leucocyte glycoprotein deficiency is a rare, congenital adhesion molecule disorder which, in its severe form, is usually fatal. Leucocytes in affected subjects have abnormal migration and adherence, rendering patients susceptible to life threatening infections. The CD11/CD18 integrins, and other adhesion molecules, are considered essential to the normal inflammatory response. It has been postulated that adhesion molecules may be responsible for mediating in part, the inflammatory changes observed in inflammatory bowel diseases and related disorders. This report describes the first case of CD11/CD18 deficiency characterised by a chronic ileocolitis. Bone marrow transplantation completely resolved the gastrointestinal symptoms, supporting a role for neutrophil dysfunction in the pathogenesis of the gut lesions. This case suggests that specific blockade of CD11/CD18 integrins alone may not halt the chronic inflammatory response observed in immune mediated bowel disorders, and that abnormalities of leucocyte function must be included in the differential diagnosis of paediatric Crohn's disease.
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Affiliation(s)
- I D D'Agata
- Division of Paediatric, Gastroenterology, Hôpital Ste-Justine, Montreal, Canada
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Nielsen OH, Brynskov J, Vainer B. Increased mucosal concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), sE-selectin, and interleukin-8 in active ulcerative colitis. Dig Dis Sci 1996; 41:1780-5. [PMID: 8794794 DOI: 10.1007/bf02088745] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Cell surface adhesion molecules (CAM) are important promotors of the immunoinflammatory cascade. The circulating levels of soluble intercellular adhesion molecule 1 (ICAM-1) have previously been shown to correlate with disease activity in inflammatory bowel disease. The primary aim of this study was consequently to investigate if this also applies to mucosal levels of soluble ICAM-1. We measured soluble ICAM-1 levels in intestinal biopsy specimens and the endoscopic activity of 69 patients with ulcerative colitis (UC) and 14 controls and found that the median concentration of soluble ICAM-1 was significantly higher in patients with moderately or very active UC (15.0 ng/ml) as compared to slightly active (9.8 ng/ml) and inactive UC (9.5 ng/ml) as well as controls (6.5 ng/ml) (P < 0.005). To further elucidate the interactions, two other CAM [E-selectin and vascular cellular adhesion molecule 1 (VCAM-1)], together with interleukin-8 (IL-8), IL-2 receptor (IL-2R) alpha and beta chains, were also measured. A significant trend towards higher soluble E-selectin levels in biopsies with active UC (1.8 pg/ml) as compared to inactive UC (1.3 pg/ml) and to controls (< 1.0 pg/ml) (P < 0.01) was also found. In contrast, soluble VCAM-1 was barely detectable in biopsies from two UC patients. A significant correlation was found between soluble ICAM-1 and IL-8 concentrations (r = 0.46; P < 0.0001), and between sICAM-1 and sIL-2R alpha concentrations (r = 0.69; P < 0.0001), while sIL-2R beta was not detected. This study shows that intestinal ICAM-1 and E-selectin correlate with endoscopic activity of UC and with IL-8 and IL-2R alpha levels. These mediators may be useful in monitoring mucosal inflammation in studies exploring the therapeutical potential of targeting CAM. The lack of detectable VCAM-1, which is induced only in venous endothelium is interesting. It may suggest that intestinal inflammation mainly affects arterial endothelial cells and support the theory that intestinal vasculitis is involved in the pathogenesis of inflammatory bowel disease.
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Affiliation(s)
- O H Nielsen
- Department of Gastroenterology F, Glostrup Hospital, University of Copenhagen, Denmark
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Davidsen B, Munkholm P, Schlichting P, Nielsen OH, Krarup H, Bonnevie-Nielsen V. Tolerability of interferon alpha-2b, a possible new treatment of active Crohn's disease. Aliment Pharmacol Ther 1995; 9:75-9. [PMID: 7766748 DOI: 10.1111/j.1365-2036.1995.tb00355.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS Due to the need for new principles for the treatment of Crohn's disease and due to the documented immunomodulatory effects of interferon alpha, the tolerability and effect(s) of interferon alpha-2b (Introna) in active Crohn's disease were examined in a pilot study. METHODS Five patients with active Crohn's disease (activity index (CDAI) scores of 235-517), were treated with interferon alpha-2b for 12 weeks. RESULTS All patients tolerated the treatment, but developed influenza-like symptoms, which were fully controlled by paracetamol. Two patients obtained partial remission with a decline in activity index scores of 39% and 50%. The activity of 2',5'-oligoadenylate synthetase, which together with two other interferon-induced proteins, neopterin and beta 2-microglobulin were increased during treatment, indicated clearly an in vivo uptake of interferon. Sedimentation rate, C-reactive protein, orosomucoid, albumin, specific inflammatory markers: soluble interleukin-2 alpha-receptors (sIL-2R) and intercellular adhesion molecule-1 (ICAM-1) did not show any changes before or after treatment. CONCLUSION Future multicentre investigations are required to evaluate the clinical effect of interferon alpha-2b treatment in active Crohn's disease.
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Affiliation(s)
- B Davidsen
- Department of Medical Gastroenterology C. Herlev Hospital, University of Copenhagen, Denmark
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