Generic Portal

TY - JOUR

T1 - Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule

AU - Braat, Henri

AU - McGuirk, Peter

AU - ten Kate, Fiebo J. W.

AU - Huibregtse, Inge

AU - Dunne, Padraic J.

AU - Hommes, Daan W.

AU - van Deventer, Sander J. H.

AU - Mills, Kingston H. G.

PY - 2007

Y1 - 2007

N2 - 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 beta 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

AB - 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 beta 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

U2 - 10.1136/gut.2006.099861

DO - 10.1136/gut.2006.099861

M3 - Article

C2 - 16952913

VL - 56

SP - 351

EP - 357

JO - Gut

JF - Gut

SN - 0017-5749

IS - 3

ER -