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Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease
  1. S Kugathasan1,
  2. L J Saubermann6,
  3. L Smith3,
  4. D Kou4,
  5. J Itoh4,
  6. D G Binion5,
  7. A D Levine4,
  8. R S Blumberg2,
  9. C Fiocchi7
  1. 1
    Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
  2. 2
    Gastroenterology Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  3. 3
    Apollon, Inc., Wyeth-Lederle Vaccines & Pediatrics, One Great Valley Parkway, Malvern, Pennsylvania 19355, USA
  4. 4
    Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA
  5. 5
    Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
  6. 6
    Division of Gastroenterology, University of Rochester, Rochester, New York 02118, USA
  7. 7
    Department of Pathobiology, Lerner Research Institute, and Department of Gastroenterology & Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
  1. Dr Claudio Fiocchi, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA; fiocchc{at}ccf.org

Abstract

Background and aims: Crohn’s disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn’s disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn’s disease.

Methods: Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn’s disease, children with long-standing Crohn’s disease, infectious colitis, and children without gut inflammation.

Results: As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn’s disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-γ production and IL12Rβ2 chain expression. Th1 polarisation was not induced in clones from late Crohn’s disease. Mucosal levels of IL12p40 and IL12Rβ2 messenger RNA were significantly higher in children with early than late Crohn’s disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn’s disease.

Conclusions: At the onset of Crohn’s disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn’s disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.

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Footnotes

  • Funding: This work was supported by grants from the National Institutes of Health (DK30399, DK50984 and DK57756 to C F; DK54213 to A D L; DK44319 and DK51362 to R B). L J S is a Howard Hughes Medical Institute Physician Postdoctoral Fellow.

  • Competing interests: None.

  • Abbreviations:
    CD
    Crohn’s disease
    CDR3
    complementary determining region 3
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    IBD
    inflammatory bowel disease
    PBMC
    peripheral blood mononuclear cell
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    RT
    reverse transcriptase
    Th
    T helper
    TLR
    Toll-like receptor

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