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      Treatment of Crohn’s disease with colony-stimulating factors: An overview

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          Abstract

          Current treatments for Crohn’s disease are aimed at suppressing excessive immune activation in the bowel walls. However, alternative strategies can be drawn. These involve the augmentation of the innate immune response, in the hypothesis that patients affected with Crohn’s disease are characterized by a relative immunodeficiency, with failure of the defensive barrier to luminal microbes and microbial products, resulting in a chronic inflammatory process sustained by T-cells. Alternatively, therapy could act by enhancing the number or the activity of subpopulations of T regulatory cells, able to reduce T-cell activation. Colony-stimulating factors are substances that could be efficacious in these settings. In fact, besides in vitro and animal studies, some human studies have been conducted in recent years with both granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor, the results of which are reported here.

          Most cited references34

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          Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

          Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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            A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.

            Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.
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              Inflammatory bowel disease.

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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                October 2008
                October 2008
                : 4
                : 5
                : 927-934
                Affiliations
                [1 ]Department of Internal Medicine, Operative Unit of Gastroenterology and
                [2 ]Department of Hematology, Laboratory of Immunology, Università Cattolica del Sacro Cuore, Rome, Italy
                Author notes
                Correspondence: Luisa Guidi, Università Cattolica del Sacro Cuore, Istituto di Medicina Interna e Geriatria, Largo A. Gemelli, 8, 00168, Roma, Italia, Tel +39 6350 3239, Fax +39 6305 4641, Email lguidi@ 123456rm.unicatt.it
                Article
                tcrm-4-927
                2621411
                19209275
                e7344d89-45d5-48d2-8ced-f7bb00d8c2ce
                © 2008 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Medicine
                inflammatory bowel disease,gm-csf,g-csf,crohn’s disease treatment
                Medicine
                inflammatory bowel disease, gm-csf, g-csf, crohn’s disease treatment

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