Gastroenterology
Volume 136, Issue 1 , Pages 278-287 , January 2009

CpG Motifs of Bacterial DNA Exert Protective Effects in Mouse Models of IBD by Antigen-Independent Tolerance Induction

  • Andre Bleich

      Affiliations

    • Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
    • Corresponding Author InformationAddress requests for reprints to: Andre Bleich, Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. fax: +49 511 532 3710
  • ,
  • Lydia M. Janus

      Affiliations

    • Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
  • ,
  • Anna Smoczek

      Affiliations

    • Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
  • ,
  • Astrid M. Westendorf

      Affiliations

    • Department Mucosal Immunity, Helmholtz Centre for Infection Research, Braunschweig, and Institute of Medical Microbiology, University Hospital Essen, Essen, Germany
  • ,
  • Ulrike Strauch

      Affiliations

    • Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
  • ,
  • Michael Mähler

      Affiliations

    • Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
  • ,
  • Hans-J. Hedrich

      Affiliations

    • Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
  • ,
  • Stefan Fichtner-Feigl

      Affiliations

    • Department of Surgery, University of Regensburg, Regensburg, Germany
  • ,
  • Jürgen Schölmerich

      Affiliations

    • Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
  • ,
  • Werner Falk

      Affiliations

    • Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
  • ,
  • Claudia Hofmann

      Affiliations

    • Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
  • ,
  • Florian Obermeier

      Affiliations

    • Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Received 22 January 2008 ,Accepted 18 September 2008.

References 

  1. Andus T, Gross V. Etiology and pathophysiology of inflammatory bowel disease--environmental factors. Hepatogastroenterology. 2000;47:29–43
  2. Sartor RB. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol. 1997;92:5S–11S
  3. Bleich A, Mähler M. Environment as a critical factor for the pathogenesis and outcome of gastrointestinal disease: experimental and human inflammatory bowel disease and Helicobacter-induced gastritis. Pathobiology. 2005;72:293–307
  4. Cong Y, Brandwein SL, McCabe RP, et al. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med. 1998;187:855–864
  5. Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2 (Implications for Crohn's disease). J Biol Chem. 2003;278:5509–5512
  6. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869–8872
  7. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603–606
  8. Krieg AM. Now I know my CpGs. Trends Microbiol. 2001;9:249–252
  9. Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995;374:546–549
  10. Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–745
  11. Bauer S, Wagner H. Bacterial CpG-DNA licenses TLR9. Curr Top Microbiol Immunol. 2002;270:145–154
  12. O'Hagan DT, MacKichan ML, Singh M. Recent developments in adjuvants for vaccines against infectious diseases. Biomol Eng. 2001;18:69–85
  13. Krieg AM. From bugs to drugs: therapeutic immunomodulation with oligodeoxynucleotides containing CpG sequences from bacterial DNA. Antisense Nucleic Acid Drug Dev. 2001;11:181–188
  14. Metzger WJ, Nyce JW. Oligonucleotide therapy of allergic asthma. J Allergy Clin Immunol. 1999;104:260–266
  15. Creticos PS, Schroeder JT, Hamilton RG, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006;355:1445–1455
  16. Katakura K, Sato Y, Sato N. CpG motifs in plasmid DNA exacerbate inflammation in experimental colitis. Gastroenterology. 2001;120:A.518
  17. Obermeier F, Dunger N, Strauch UG, et al. Contrasting activity of cytosin-guanosin dinucleotide oligonucleotides in mice with experimental colitis. Clin Exp Immunol. 2003;134:217–224
  18. Rachmilewitz D, Karmeli F, Takabayashi K, et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology. 2002;122:1428–1441
  19. Obermeier F, Strauch UG, Dunger N, et al. In vivo CpG DNA/toll-like receptor 9 interaction induces regulatory properties in CD4+CD62L+ T cells which prevent intestinal inflammation in the SCID transfer model of colitis. Gut. 2005;54:1428–1436
  20. Nicklas W, Baneux P, Boot R, et al. Recommendations for the health monitoring of rodent and rabbit colonies in breeding and experimental units. Lab Anim. 2002;36:20–42
  21. Sparwasser T, Koch ES, Vabulas RM, et al. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol. 1998;28:2045–2054
  22. Kawade Y, Watanabe Y. Characterization of rat monoclonal antibodies to mouse interferon a and b (Proceedings of the Third International TNO Meeting on the Biology of the Interferon System). In:  Cantell K,  Schellekens H editor. The Biology of the Interferon System. Dordrecht: Martinus Nijhoff; 1987;p. 197–201
  23. Fuss IJ, Boirivant M, Lacy B, et al. The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis. J Immunol. 2002;168:900–908
  24. Bleich A, Mähler M, Most C, et al. Refined histopathologic scoring system improves power to detect colitis QTL in mice. Mamm Genome. 2004;15:865–871
  25. Moolenbeek C, Ruitenberg EJ. The “Swiss roll”: a simple technique for histological studies of the rodent intestine. Lab Anim. 1981;15:57–59
  26. de Buhr MF, Mähler M, Geffers R, et al. Cd14, Gbp1, and Pla2g2a: three major candidate genes for experimental IBD identified by combining QTL and microarray analyses. Physiol Genomics. 2006;25:426–434
  27. Katakura K, Lee J, Rachmilewitz D, et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest. 2005;115:695–702
  28. Levings MK, Sangregorio R, Galbiati F, et al. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol. 2001;166:5530–5539
  29. Bilsborough J, George TC, Norment A, et al. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology. 2003;108:481–492
  30. Yamagiwa S, Gray JD, Hashimoto S, et al. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol. 2001;166:7282–7289
  31. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–1886
  32. Moseman EA, Liang X, Dawson AJ, et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol. 2004;173:4433–4442
  33. Strauch UG, Obermeier F, Grunwald N, et al. Influence of intestinal bacteria on induction of regulatory T cells: lessons from a transfer model of colitis. Gut. 2005;54:1546–1552
  34. Mudter J, Neurath MF. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis. 2007;13:1016–1023
  35. Rose S, Lichtenheld M, Foote MR, et al. Murine neonatal CD4+ cells are poised for rapid Th2 effector-like function. J Immunol. 2007;178:2667–2678
  36. Sudo N, Sawamura S, Tanaka K, et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol. 1997;159:1739–1745
  37. Fort M, Lesley R, Davidson N, et al. IL-4 exacerbates disease in a Th1 cell transfer model of colitis. J Immunol. 2001;166:2793–2800
  38. Roers A, Siewe L, Strittmatter E, et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J Exp Med. 2004;200:1289–1297

 C.H. and F.O. contributed equally to the work.

 The authors disclose the following: Supported by grants from the DFG (O.B. 135/10-1, F.O.; SFB621, H.H.) and the German Crohn′s and Colitis Foundation (DCCV, F.O.). The authors gratefully acknowledge the excellent technical assistance of N. Dunger.

PII: S0016-5085(08)01691-0

doi: 10.1053/j.gastro.2008.09.022

Gastroenterology
Volume 136, Issue 1 , Pages 278-287 , January 2009