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. 1999 Oct 4;190(7):953-62.
doi: 10.1084/jem.190.7.953.

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

D Artis  1 , N E Humphreys, A J Bancroft, N J Rothwell, C S Potten, R K Grencis
Affiliations

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

D Artis et al. J Exp Med. .

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.

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Figures

Figure 1
Figure 1
Mean worm burden ± SEM in C57BL/6 mice treated with either PBS, anti–TNF-α, or control Ig. 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 19 p.i. Worm burdens from four mice per group were determined on days 21 (A) and 35 (B). *Significantly higher worm burden than control treated mice (P < 0.05).
Figure 2
Figure 2
Cytokine production from T. muris–infected C57BL/6 mice after treatment with PBS, anti–TNF-α, or control Ig. Mesenteric lymph node cells were removed on day 21 p.i., stimulated in vitro with 50 μg T. muris Ag for 24 h, and supernatants were analyzed by sandwich ELISA for the presence of IL-4 (A), IL-5 (B), IL-9 (C), and IL-13 (D). Results represent the mean values of four mice per group ± SEM. *Significantly lower than control treated groups (P < 0.05).
Figure 3
Figure 3
Ag-specific IgG isotype responses from naive (⋄) and T. muris–infected C57BL/6 mice after treatment with PBS (▴), anti–TNF-α (•), or control Ig (▪). Serum was collected from naive and infected mice at day 35 p.i. and assayed by capture ELISA for the presence of IgG1 (A) and IgG2a (B). Results represent the mean of four mice per group ± SEM.
Figure 4
Figure 4
Mean worm burden ± SEM in TNFR KO (A) and C57BL/6 × 129 WT (B) mice on various days after infection. Mice were infected on day 0 with 200 T. muris eggs, and worm burden was assessed from four to six mice per group. *Significantly lower worm burden than KO mice at corresponding time point (P < 0.05).
Figure 5
Figure 5
Cytokine production from T. muris–infected TNFR KO and C57BL/6 × 129 WT mice. Mesenteric lymph node cells were removed on day 18 p.i., stimulated in vitro with 50 μg T. muris Ag for 24 h, and supernatants were analyzed by sandwich ELISA for the presence of IL-4 (A), IL-5 (B), IL-9 (C), and IL-13 (D). Results represent the mean values of four to six mice per group ± SEM. *Significantly lower than WT values (P < 0.05).
Figure 7
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).
Figure 6
Figure 6
Ag-specific IgG isotype responses from T. muris–infected TNFR KO (•) and C57BL/6 × 129 WT (▪) mice (naive KO [⋄] and naive WT [+]). Serum was collected from naive and infected mice at day 35 p.i. and assayed by capture ELISA for the presence of IgG1 (A) and IgG2a (B). Results represent the mean of four to six mice per group ± SEM.
Figure 8
Figure 8
Cytokine production from T. muris–infected female BALB/c IL-4 KO mice after treatment with anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mesenteric lymph node cells were removed on day 18 p.i., stimulated in vitro with 50 μg T. muris Ag for 24 h, and supernatants were analyzed by sandwich ELISA for the presence of IL-5 (A), IL-9 (B), and IL-13 (C). Results represent the mean values from four mice per group ± SEM. *Significantly lower than control treated groups (P < 0.05).
Figure 8
Figure 8
Cytokine production from T. muris–infected female BALB/c IL-4 KO mice after treatment with anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mesenteric lymph node cells were removed on day 18 p.i., stimulated in vitro with 50 μg T. muris Ag for 24 h, and supernatants were analyzed by sandwich ELISA for the presence of IL-5 (A), IL-9 (B), and IL-13 (C). Results represent the mean values from four mice per group ± SEM. *Significantly lower than control treated groups (P < 0.05).
Figure 8
Figure 8
Cytokine production from T. muris–infected female BALB/c IL-4 KO mice after treatment with anti–TNF-α (black bars), control Ig (stippled bars), or PBS (striped bars). Mesenteric lymph node cells were removed on day 18 p.i., stimulated in vitro with 50 μg T. muris Ag for 24 h, and supernatants were analyzed by sandwich ELISA for the presence of IL-5 (A), IL-9 (B), and IL-13 (C). Results represent the mean values from four mice per group ± SEM. *Significantly lower than control treated groups (P < 0.05).
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References

    1. Abbas A.K., Murphy K.M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787–793. - PubMed
    1. Mosmann T., Sad S. The expanding universe of T-cell subsetsTh1, Th2 and more. Immunol. Today. 1996;17:138–146. - PubMed
    1. O'Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity. 1998;8:275–283. - PubMed
    1. Else K.J., Hültner L.H., Grencis R.K. Modulation of cytokine production and response phenotypes in murine trichuriasis. Parasite Immunol. 1992;14:441–449. - PubMed
    1. Else K.J., Finkelman F.D., Maliszewski C.R., Grencis R.K. Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med. 1994;179:347–351. - PMC - PubMed

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