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      Preventive Anti-CD2 Treatment does not Impair Parasite Control in a Murine Toxoplasmosis Model


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          Targeting human CD2 with the monoclonal antibody (mAb) CB.219 reduces intestinal inflammation in a colitis model where T cells carry human CD2. Here, we asked whether this mAb has adverse effects on infection control.

          Mice expressing human CD2 on T cells (huCD2tg) were orally infected with Toxoplasma ( T.) gondii and treated with the human CD2-specific mAb CB.219 in a preventive setting. The intestinal T. gondii loads in CB.219 treated mice did not differ from the control group. Histologically, huCD2tg mice showed moderate ileal inflammation that did not change with CB.219 treatment. In the ileum, CB.219 treatment reduced the protein levels of interferon-γ, transforming growth factor β and interleukin-6, whereas interleukin-18 mRNA was slightly increased. The infiltration of neutrophils, macrophages, and T cells into the ileum was unaffected by CB.219 treatment. However, CB.219 treatment decreased the numbers of forkhead box P3 + regulatory T cells (Treg) in ileum and liver of huCD2tg mice. This was confirmed in vitro using human peripheral blood mononuclear cells.

          Taken together, targeting CD2 + T cells by the human CD2 mAb CB.219 does not prevent beneficial immune reactions necessary for pathogen control. Further experiments will address gut specificity, underlying mechanisms, and general applicability of CB.219 treatment.

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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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            Chronic hepatitis. An update on terminology and reporting.

            The terms chronic active hepatitis (CAH), chronic persistent hepatitis (CpH), and chronic lobular hepatitis (CLH) have become obsolete, and their use without further specifications should be discontinued. This recommendation has become necessary because these names have changed from descriptive terms, intended for grading, to terms that are used either as morphologic diagnoses or disease designations or both, depending on individual preferences. Because this practice has caused serious misunderstandings, many authors and two international groups have recommended the use of a clear etiologic terminology. For the reporting practice of pathologists, we recommend that the pathologist routinely sign out biopsy samples with features of chronic hepatitis by indicating etiology, grade, and stage. An example would be autoimmune hepatitis, severe, stage 3. The stage in this case would indicate the presence of well-developed septal fibrosis but no nodular regeneration. Obviously, for the etiologic diagnosis, morphologic findings must be integrated with clinical and laboratory data. If this information is not available, clear morphologic diagnoses should be reported. Thus, instead of CPH, the diagnosis should be portal hepatitis, cause undetermined. This reporting practice eliminates ambiguous terminology and avoids the risk of inappropriate treatment as might occur, for example, when a term such as CAH is used to describe Wilson's disease and is misunderstood to mean autoimmune hepatitis. For a transitional period and to facilitate relearning, the terms CAH, CPH, and CLH can be reported in parentheses behind the etiologic diagnosis.
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              Interleukin (IL)-23 mediates Toxoplasma gondii–induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

              Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.

                Author and article information

                Eur J Microbiol Immunol (Bp)
                Eur J Microbiol Immunol (Bp)
                European Journal of Microbiology & Immunology
                Akadémiai Kiadó (Budapest )
                12 November 2015
                December 2015
                : 5
                : 4
                : 306-315
                [1 ] Medical Department (Gastroenterology, Infectious Diseases, Rheumatology), Campus Benjamin Franklin, Chari té – Universitätsmedizin Berlin , Berlin, Germany
                [2 ] Research Center ImmunoSciences, Charité – Universitätsmedizin Berlin , Berlin, Germany
                [3 ]Immatics Biotechnologies GmbH , Tübingen, Germany
                [4 ] Institute for Microbiology and Hygiene, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin , Berlin, Germany
                [5 ]Pathotres Joint Practice for Pathology , Berlin, Germany
                [6 ]Cold Spring Harbor Laboratory , Cold Spring Harbor, New York, USA
                Author notes
                * Medical Department (Gastroenterology, Infectious Diseases, Rheumatology), Campus Benjamin Franklin, Charité – Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; +49(0)30 450-514345; +49(0)30 450-514904; anja.kuehl@ 123456charite.de
                © 2015, The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 13 October 2015
                : 23 October 2015
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 31, Pages: 10
                Original Article

                cd2,inflammatory bowel disease,infection model,experimental ileitis


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