Limits...
Tumor necrosis factor alpha is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection.

Artis D, Humphreys NE, Bancroft AJ, Rothwell NJ, Potten CS, Grencis RK - J. Exp. Med. (1999)

Bottom Line: In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response.In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment.These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.

View Article: PubMed Central - PubMed

Affiliation: Immunology Group, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. mqbsszda@man.ac.uk

ABSTRACT
In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti-TNF-alpha monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-alpha in regulation of Th2 cytokine-mediated host protection. In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13-mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-alpha dependent, and could be enhanced by administration of recombinant TNF-alpha. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.

Show MeSH

Related in: MedlinePlus

Mean worm burden ± SEM in female BALB/c IL-4 KO mice treated with either anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mice were infected on day 0 with 200 T. muris eggs and treated intraperitoneally with 2 mg mAb every 3 d between days 7 and 28 p.i. Worm burdens from four mice per group were determined on days 18, 22, and 35 p.i. *Significantly lower worm burden than anti–TNF-α treated groups (P < 0.05).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2195648&req=5

Figure 7: Mean worm burden ± SEM in female BALB/c IL-4 KO mice treated with either anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mice were infected on day 0 with 200 T. muris eggs and treated intraperitoneally with 2 mg mAb every 3 d between days 7 and 28 p.i. Worm burdens from four mice per group were determined on days 18, 22, and 35 p.i. *Significantly lower worm burden than anti–TNF-α treated groups (P < 0.05).

Mentions: Blockade of TNF-α in female BALB/c IL-4 KO mice significantly prevented worm expulsion (Fig. 7 C). In accordance with previously unpublished data, in control treated IL-4 KO mice worm expulsion was initiated around day 22 p.i. (Fig. 7 B), and approximately 60% of worms were cleared by day 35 p.i. (Fig. 7 C). Ag-specific cytokine production by mesenteric lymph node cells at day 18 p.i. showed comparable Th2 responses in the different treatment groups (Fig. 8), although IL-9 and IL-13 production was lower in anti–TNF-α treated mice than in the control Ig group (primarily as a result of the variability observed in this group; Fig. 8b and Fig. c). No difference in the IgG1 response was observed between anti–TNF-α and control treated groups (data not shown), supporting the hypothesis that TNF-α blockade did not alter the generation of Th2 responses, but may be critical at the effector stage in the intestine. Comparable and relatively high IgG2a responses were observed in all groups (data not shown), reflecting the production of Th1 cytokines as previously reported in T. muris–infected C57BL/6 IL-4 KO mice 7.


Tumor necrosis factor alpha is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection.

Artis D, Humphreys NE, Bancroft AJ, Rothwell NJ, Potten CS, Grencis RK - J. Exp. Med. (1999)

Mean worm burden ± SEM in female BALB/c IL-4 KO mice treated with either anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mice were infected on day 0 with 200 T. muris eggs and treated intraperitoneally with 2 mg mAb every 3 d between days 7 and 28 p.i. Worm burdens from four mice per group were determined on days 18, 22, and 35 p.i. *Significantly lower worm burden than anti–TNF-α treated groups (P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195648&req=5

Figure 7: Mean worm burden ± SEM in female BALB/c IL-4 KO mice treated with either anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mice were infected on day 0 with 200 T. muris eggs and treated intraperitoneally with 2 mg mAb every 3 d between days 7 and 28 p.i. Worm burdens from four mice per group were determined on days 18, 22, and 35 p.i. *Significantly lower worm burden than anti–TNF-α treated groups (P < 0.05).
Mentions: Blockade of TNF-α in female BALB/c IL-4 KO mice significantly prevented worm expulsion (Fig. 7 C). In accordance with previously unpublished data, in control treated IL-4 KO mice worm expulsion was initiated around day 22 p.i. (Fig. 7 B), and approximately 60% of worms were cleared by day 35 p.i. (Fig. 7 C). Ag-specific cytokine production by mesenteric lymph node cells at day 18 p.i. showed comparable Th2 responses in the different treatment groups (Fig. 8), although IL-9 and IL-13 production was lower in anti–TNF-α treated mice than in the control Ig group (primarily as a result of the variability observed in this group; Fig. 8b and Fig. c). No difference in the IgG1 response was observed between anti–TNF-α and control treated groups (data not shown), supporting the hypothesis that TNF-α blockade did not alter the generation of Th2 responses, but may be critical at the effector stage in the intestine. Comparable and relatively high IgG2a responses were observed in all groups (data not shown), reflecting the production of Th1 cytokines as previously reported in T. muris–infected C57BL/6 IL-4 KO mice 7.

Bottom Line: In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response.In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment.These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.

View Article: PubMed Central - PubMed

Affiliation: Immunology Group, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. mqbsszda@man.ac.uk

ABSTRACT
In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti-TNF-alpha monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-alpha in regulation of Th2 cytokine-mediated host protection. In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13-mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-alpha dependent, and could be enhanced by administration of recombinant TNF-alpha. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.

Show MeSH
Related in: MedlinePlus