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      Treatment with interleukin-18 binding protein ameliorates Toxoplasma gondii-induced small intestinal pathology that is induced by bone marrow cell-derived interleukin-18


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          Peroral infection with Toxoplasma gondii results in a Th1-type immunopathology characterized by small intestinal necrosis and is dependent on IL-18. In the present study, we investigated whether treatment with IL-18 binding protein (IL-18bp) prevents ileal pathology. We observed increased expression of IL-18bp in intestinal biopsies of mice following infection. Whereas small intestines of control mice showed severe necrosis with complete destruction of the small intestinal architecture, mice treated with IL-18bp daily displayed only mild inflammatory changes including flattening of villi and edema in the space between the epithelium and lamina propria. Small intestinal parasite loads and concentrations of pro-inflammatory cytokines did not differ in control and IL-18bptreated mice. Binding of IL-18 to immobilized IL-18bp revealed a remarkably slow dissociation rate, indicating high affinity. Using chimeric mice we observed that bone marrow-derived rather than stromal cells were the primary source of IL-18 that resulted in small intestinal pathology following peroral infection with T. gondii. In conclusion, the results presented here suggest that IL-18bp may be an effective and safe treatment for small intestinal inflammation. Antigen-presenting rather than epithelial cells appear to be the main source of IL-18 in T. gondii-induced small intestinal inflammation.

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          Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii.

          Oral infection of susceptible mice with Toxoplasma gondii results in Th1-type immunopathology in the ileum. We investigated gut flora changes during ileitis and determined contributions of gut bacteria to intestinal inflammation. Analysis of the intestinal microflora revealed that ileitis was accompanied by increasing bacterial load, decreasing species diversity, and bacterial translocation. Gram-negative bacteria identified as Escherichia coli and Bacteroides/Prevotella spp. accumulated in inflamed ileum at high concentrations. Prophylactic or therapeutic administration of ciprofloxacin and/or metronidazole ameliorated ileal immunopathology and reduced intestinal NO and IFN-gamma levels. Most strikingly, gnotobiotic mice in which cultivable gut bacteria were removed by quintuple antibiotic treatment did not develop ileitis after Toxoplasma gondii infection. A reduction in total numbers of lymphocytes was observed in the lamina propria of specific pathogen-free (SPF), but not gnotobiotic, mice upon development of ileitis. Relative numbers of CD4(+) T cells did not differ in naive vs infected gnotobiotic or SPF mice, but infected SPF mice showed a significant increase in the frequencies of activated CD4(+) T cells compared with gnotobiotic mice. Furthermore, recolonization with total gut flora, E. coli, or Bacteroides/Prevotella spp., but not Lactobacillus johnsonii, induced immunopathology in gnotobiotic mice. Animals recolonized with E. coli and/or total gut flora, but not L. johnsonii, showed elevated ileal NO and/or IFN-gamma levels. In conclusion, Gram-negative bacteria, i.e., E. coli, aggravate pathogen-induced intestinal Th1-type immunopathology. Thus, pathogen-induced acute ileitis may prove useful to study bacteria-host interactions in small intestinal inflammation and to test novel therapies based on modulation of gut flora.
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            IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells.

            IL-18, a novel immunoregulatory cytokine with potent IFN-gamma-inducing activities, may play an important role in Th1-mediated chronic inflammatory disorders. The aim of the present study was to characterize the expression and localization of IL-18 in colonic specimens and isolated mucosal cell populations from patients with Crohn's disease (CD), a prototypic Th1-mediated disorder. Using a semiquantitative RT-PCR protocol, IL-18 mRNA transcripts were found to be increased in freshly isolated intestinal epithelial cells (IEC) and lamina propria mononuclear cells (LPMC) from CD compared with ulcerative colitis (UC) and noninflamed control (cont) patients, and were more abundant in IEC compared with LPMC. Immunohistochemical analysis of surgically resected colonic tissues localized IL-18 to both LPMC (specifically, macrophages and dendritic cells) as well as IEC. Staining was more intense in CD compared with UC and cont, and in involved (inv) vs noninvolved (n inv) areas. Western blot analysis revealed that an 18. 3-kDa band, consistent with both recombinant and mature human IL-18 protein, was found predominantly in CD vs UC intestinal mucosal biopsies; a second band of 24 kDa, consistent with the inactive IL-18 precursor, was detected in n inv areas from both CD and UC biopsies and was the sole form found in noninflamed cont. To our knowledge, this report is the first describing increased expression of IL-18 in a human Th1-mediated chronic inflammatory disease. In addition, our studies further support the concept that IEC and dendritic cells may possess important immunoregulatory functions in both normal, as well as pathological, mucosal immunity.
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              Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure.

              A cDNA encoding the CD2 antigen has been isolated by a highly efficient technique based on transient expression in COS cells and adherence of cells expressing surface antigen to antibody-coated dishes. COS cells expressing a CD2 cDNA isolated by this method readily formed rosettes with sheep as well as human and other mammalian erythrocytes. Pretreatment of transfected COS cells with anti-CD2 antibody, or pretreatment of human erythrocytes with anti-LFA-3 antibody, abolished rosette formation.

                Author and article information

                European Journal of Microbiology and Immunology
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                1 September 2012
                : 2
                : 3
                : 249-257
                [ 1 ] Institut für Mikrobiologie und Hygiene, Charité — Campus Benjamin Franklin, Berlin, Germany
                [ 2 ] Institut für Laboratoriumsmedizin und Pathobiochemie, Charité — Campus Benjamin Franklin, Berlin, Germany
                [ 3 ] Abteilung Immunologie, Max-Planck Institut für Infektionsbiologie Berlin, Berlin, Germany
                [ 4 ] Abteilung für Gastroenterologie, Hepatologie and Infektiologie, Klinik für Innere Medizin II, Universitätsklinikum Jena der Friedrich Schiller Universität Jena, Jena, Germany
                [ 5 ] Institut für Medizinische Mikrobiologie und Krankenhaushygiene der Philipps Universität Marburg, Hans-Meerwein Straße 2, 35032, Marburg, Germany
                [ 6 ] Medical and Scientific Affairs, Roche Molecular Diagnostics, Pleasanton, CA, USA
                [ 7 ] Institut für Mikrobiologie und Hygiene, Charité — Campus Benjamin Franklin, Hindenburgdamm 27, D-12203, Berlin, Germany
                Author notes

                These authors contributed equally to this work.

                [* ] +49-30-844-53628, +49-30-844-53620, oliver.liesenfeld@ 123456charite.de
                : 19 June 2012
                : 29 June 2012
                Original Articles

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                immunopathology,IL-18,ileitis,IL-18 binding protein, Toxoplasma gondii


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