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

Henri Braat ^1*, Peter McGuirk ², Fiebo ten Kate ¹, Inge Huibregtse ¹, Padraic Dunne ², Daan Hommes ¹, Sander Deventer ¹ and Kingston Mills ²

¹ Academic Medical Center, Amsterdam, Netherlands
² Trinity College, Dublin, Eire

^* To whom correspondence should be addressed. E-mail: gahib{at}slz.nl.

Accepted 1 August 2006

Abstract

Background and aims: Filamentous haemagglutinin (FHA) of Bordetella pertussis subverts host immune responses by inhibiting interleukin (IL)-12 and enhancing IL-10 production by macrophages and dendritic cells (DC) and promoting the induction of regulatory T (Tr) cells. We hypothesized that injection of FHA would ameliorate disease in a T-cell dependent model of colitis via the induction of anti-inflammatory cytokines and Tr cells.

Methods: Colitis was induced by injection of CD4+CD45RBhigh naïve T-cells into severe combined immunodeficient (SCID) mice. Mice were treated with four subcutaneous injections of FHA or buffer only.

Results: Parenteral injection of FHA stimulated IL- 10 and/or transforming growth factor (TGF)- production in local and mesenteric lymph nodes and Peyers’ patches of mice 2-6 hours after administration. Compared with PBS-treated, SCID mice treated with FHA 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 IL-10 and reduced Th1 and Th2 cytokine production by spleen cells. Finally, FHA also attenuated the symptoms of colitis in SCID mice transferred with CD4+CD45RBhigh T-cells from IL-10 deficient mice.

Conclusions: Our finding demonstrate that FHA suppresses Th1 and pro-inflammatory cytokines and ameliorates disease activity in a chronic T-cell dependent model of colitis, an effect that was not dependant on IL-10 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 humans suffering from Crohn’s disease.

Keywords: T lymphocytes, regulatory, bacterial outer membrane proteins, colitis, immunotherapy, mice

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