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Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule
  1. Henri Braat1,
  2. Peter McGuirk2,
  3. Fiebo J W Ten Kate3,
  4. Inge Huibregtse4,
  5. Padraic J Dunne2,
  6. Daan W Hommes1,
  7. Sander J H Van Deventer4,
  8. Kingston H G Mills2
  1. 1Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
  3. 3Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
  4. 4Department of Experimental Internal Medicine, Academic Medical Center, The Netherlands
  1. Correspondence to:
    Professor K H G Mills
    Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland;kingston.mills{at}tcd.ie

Abstract

Background: Filamentous haemagglutinin (FHA) of Bordetella pertussis subverts host immune responses by inhibiting interleukin (IL)12 and enhancing IL10 production by macrophages and dendritic cells, and promoting the induction of regulatory T cells.

Hypothesis: Injection of FHA would ameliorate disease in a T cell-dependent model of colitis via the induction of anti-inflammatory cytokines and regulatory T cells.

Methods: Colitis was induced by injection of CD4CD45RBhigh naive T cells into severe combined immunodeficient (SCID) mice. Mice were treated with four subcutaneous injections of FHA or buffer alone.

Results: Parenteral injection of FHA stimulated IL10 and/or transforming growth factor β production in local and mesenteric lymph nodes and Peyer’s patches of mice 2–6 h after administration. Compared with phosphate-buffered saline-treated mice, FHA-treated SCID mice had significantly (p<0.01) less weight loss, lower colon weight, less colon shrinkage and reduced inflammatory lesions. The therapeutic effect of FHA was associated with enhanced IL10 and reduced type 1 and type 2 T helper cytokine production by spleen cells. Finally, FHA also attenuated the symptoms of colitis in SCID mice transferred with CD4CD45RBhigh T cells from IL10-deficient mice.

Conclusions: Our finding shows that FHA suppresses type 1 T helper and pro-inflammatory cytokines, and ameliorates disease activity in a chronic T cell-dependent model of colitis, an effect that was not dependent on IL10 production by T cells, but was associated with induction of anti-inflammatory cytokines in vivo. Having already been used as a pertussis vaccine component in children, FHA is a promising candidate for clinical testing in patients with Crohn’s disease.

  • FHA, filamentous haemagglutinin
  • IFN, interferon
  • IL10−/−, interleukin-10-defective
  • PBS, phosphate-buffered-saline
  • Th1, type 1 T helper cell
  • TGF, transforming growth factor
  • TLR, Toll-like receptor
  • TNF, tumour necrosis factor
  • SCID, severe combined immunodeficient

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Footnotes

  • Published Online First 4 September 2006

  • Funding: PM and KHGM are supported by Science Foundation Ireland. PD is supported by the Irish Health Research Board. HB is supported by an unrestricted educational grant from the Broad Medical Research Programme.

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