Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule.
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.
Braat
Henri
H
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
McGuirk
Peter
P
Ten Kate
Fiebo J W
FJ
Huibregtse
Inge
I
Dunne
Padraic J
PJ
Hommes
Daan W
DW
Van Deventer
Sander J H
SJ
Mills
Kingston H G
KH
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*
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