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Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells.

Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO - J. Exp. Med. (2008)

Bottom Line: IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro.TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic.Treatment of macrophages with rTNF also inhibited p40 production in vitro.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, London, W6 8LH, England, UK.

ABSTRACT
IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55(-/-) but not p75(-/-) mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55(-/-) mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells.

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Increased IL-17 and IFNγ production in CIA after blockade of TNFα. DBA/1 mice with CIA were treated with TNFR-Fc or isotype control mAb (100 μg/mouse on alternate days) from the time of disease onset. (A and B) LN cells were taken 10 d after disease onset and levels of IL-17 (A) and IFNγ (B) were determined by ELISA in the supernatants without further stimulation (Nil) or after stimulation with type II collagen (CII) or anti-CD3 mAb (CD3). Data show individual mice (n = 8; *, P < 0.05). (C) Clinical scores were assessed over the 10-d period in TNFR-Fc–treated and control mice. The data are representative of at least three experiments. Error bars show SEM.
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fig1: Increased IL-17 and IFNγ production in CIA after blockade of TNFα. DBA/1 mice with CIA were treated with TNFR-Fc or isotype control mAb (100 μg/mouse on alternate days) from the time of disease onset. (A and B) LN cells were taken 10 d after disease onset and levels of IL-17 (A) and IFNγ (B) were determined by ELISA in the supernatants without further stimulation (Nil) or after stimulation with type II collagen (CII) or anti-CD3 mAb (CD3). Data show individual mice (n = 8; *, P < 0.05). (C) Clinical scores were assessed over the 10-d period in TNFR-Fc–treated and control mice. The data are representative of at least three experiments. Error bars show SEM.

Mentions: To investigate the effect of blockade of TNFα on the production of IL-17, DBA/1 mice were immunized with bovine type II collagen in CFA. After onset of arthritis, mice were treated with soluble TNFR-Fc for 10 d and the production of IL-17 and IFNγ by LN cells was determined by ELISA. Significantly increased IL-17 and IFNγ production was observed after stimulation of LN cells from TNFR-Fc–treated mice with collagen or anti-CD3 mAb in vitro, and a trend toward enhanced production of these cytokines was observed even in unstimulated LN cells (Fig. 1). As expected, arthritis severity was significantly reduced in TNFR-Fc–treated mice despite the increased IL-17 and IFNγ production (Fig. 1).


Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells.

Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO - J. Exp. Med. (2008)

Increased IL-17 and IFNγ production in CIA after blockade of TNFα. DBA/1 mice with CIA were treated with TNFR-Fc or isotype control mAb (100 μg/mouse on alternate days) from the time of disease onset. (A and B) LN cells were taken 10 d after disease onset and levels of IL-17 (A) and IFNγ (B) were determined by ELISA in the supernatants without further stimulation (Nil) or after stimulation with type II collagen (CII) or anti-CD3 mAb (CD3). Data show individual mice (n = 8; *, P < 0.05). (C) Clinical scores were assessed over the 10-d period in TNFR-Fc–treated and control mice. The data are representative of at least three experiments. Error bars show SEM.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571924&req=5

fig1: Increased IL-17 and IFNγ production in CIA after blockade of TNFα. DBA/1 mice with CIA were treated with TNFR-Fc or isotype control mAb (100 μg/mouse on alternate days) from the time of disease onset. (A and B) LN cells were taken 10 d after disease onset and levels of IL-17 (A) and IFNγ (B) were determined by ELISA in the supernatants without further stimulation (Nil) or after stimulation with type II collagen (CII) or anti-CD3 mAb (CD3). Data show individual mice (n = 8; *, P < 0.05). (C) Clinical scores were assessed over the 10-d period in TNFR-Fc–treated and control mice. The data are representative of at least three experiments. Error bars show SEM.
Mentions: To investigate the effect of blockade of TNFα on the production of IL-17, DBA/1 mice were immunized with bovine type II collagen in CFA. After onset of arthritis, mice were treated with soluble TNFR-Fc for 10 d and the production of IL-17 and IFNγ by LN cells was determined by ELISA. Significantly increased IL-17 and IFNγ production was observed after stimulation of LN cells from TNFR-Fc–treated mice with collagen or anti-CD3 mAb in vitro, and a trend toward enhanced production of these cytokines was observed even in unstimulated LN cells (Fig. 1). As expected, arthritis severity was significantly reduced in TNFR-Fc–treated mice despite the increased IL-17 and IFNγ production (Fig. 1).

Bottom Line: IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro.TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic.Treatment of macrophages with rTNF also inhibited p40 production in vitro.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology Division, Imperial College London, London, W6 8LH, England, UK.

ABSTRACT
IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55(-/-) but not p75(-/-) mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55(-/-) mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells.

Show MeSH
Related in: MedlinePlus