title: Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Henri
authors.initials: H
authors.lastname: Braat
authors.forename: Peter
authors.initials: P
authors.lastname: McGuirk
authors.forename: Fiebo J W
authors.initials: FJ
authors.lastname: Ten Kate
authors.forename: Inge
authors.initials: I
authors.lastname: Huibregtse
authors.forename: Padraic J
authors.initials: PJ
authors.lastname: Dunne
authors.forename: Daan W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Sander J H
authors.initials: SJ
authors.lastname: Van Deventer
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D018829:Adhesins, Bacterial / Q000627:therapeutic use*; D000818:Animals; D001886:Bordetella pertussis / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010581:Peyer's Patches / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D010566:Virulence Factors, Bordetella / Q000627:therapeutic use*
chemical_list: D018829:Adhesins, Bacterial; D016207:Cytokines; D016212:Transforming Growth Factor beta; D010566:Virulence Factors, Bordetella; C065273:filamentous hemagglutinin adhesin, Bordetella pertussis; D016753:Interleukin-10; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1