COLONIC INFLAMMATION

Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule

Henri Braat¹, Peter McGuirk², Fiebo J W Ten Kate³, Inge Huibregtse⁴, Padraic J Dunne², Daan W Hommes¹, Sander J H Van Deventer⁴, Kingston H G Mills²

¹ Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
² Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
³ Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
⁴ Department of Experimental Internal Medicine, Academic Medical Center, The Netherlands

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

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 CD4CD45RB^high 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 ß 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 CD4CD45RB^high 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.

Abbreviations: 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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