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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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Anti-TNFα therapy prevents the accumulation of Th1/Th17 cells in the joint. Arthritic DBA/1 mice (n = 6) were treated once every 3 d for a total of 14 d with anti-TNFα mAb (TN3-19.12; 300 μg/mouse) or control Ab. CD4+ cells from the inguinal LN and joints (obtained by enzymatic digestion of synovial tissue) were analyzed for intracellular cytokine expression by flow cytometry after stimulation with PMA/ionomycin. A, CD4+IL-17+ cells in LN; B, CD4+IL-17+ cells in joints; C, CD4+INFγ+ cells in LN; D, CD4+INFγ+ cells in joints. **, P < 0.01. Data are representative of two experiments. Error bars show SEM.
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fig5: Anti-TNFα therapy prevents the accumulation of Th1/Th17 cells in the joint. Arthritic DBA/1 mice (n = 6) were treated once every 3 d for a total of 14 d with anti-TNFα mAb (TN3-19.12; 300 μg/mouse) or control Ab. CD4+ cells from the inguinal LN and joints (obtained by enzymatic digestion of synovial tissue) were analyzed for intracellular cytokine expression by flow cytometry after stimulation with PMA/ionomycin. A, CD4+IL-17+ cells in LN; B, CD4+IL-17+ cells in joints; C, CD4+INFγ+ cells in LN; D, CD4+INFγ+ cells in joints. **, P < 0.01. Data are representative of two experiments. Error bars show SEM.

Mentions: Anti-TNFα treatment of established arthritis reduced total numbers of CD4+IFNγ+ and CD4+IL-17+ cells in joints by 63% and 67%, respectively, despite being present in increased numbers in inguinal LN (Fig. 5). It was concluded that one of the mechanisms of action of anti-TNFα therapy is to inhibit immigration of pathogenic T cells to the joint or prevent their emigration from LN. It was beyond the scope of the present study to investigate the mechanisms by which anti-TNFα prevents T cell accumulation in the joint, but they are likely to include reduced chemokine and adhesion molecule expression in the joint, as has been proposed for human RA (16, 17).


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)

Anti-TNFα therapy prevents the accumulation of Th1/Th17 cells in the joint. Arthritic DBA/1 mice (n = 6) were treated once every 3 d for a total of 14 d with anti-TNFα mAb (TN3-19.12; 300 μg/mouse) or control Ab. CD4+ cells from the inguinal LN and joints (obtained by enzymatic digestion of synovial tissue) were analyzed for intracellular cytokine expression by flow cytometry after stimulation with PMA/ionomycin. A, CD4+IL-17+ cells in LN; B, CD4+IL-17+ cells in joints; C, CD4+INFγ+ cells in LN; D, CD4+INFγ+ cells in joints. **, P < 0.01. Data are representative of two experiments. Error bars show SEM.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Anti-TNFα therapy prevents the accumulation of Th1/Th17 cells in the joint. Arthritic DBA/1 mice (n = 6) were treated once every 3 d for a total of 14 d with anti-TNFα mAb (TN3-19.12; 300 μg/mouse) or control Ab. CD4+ cells from the inguinal LN and joints (obtained by enzymatic digestion of synovial tissue) were analyzed for intracellular cytokine expression by flow cytometry after stimulation with PMA/ionomycin. A, CD4+IL-17+ cells in LN; B, CD4+IL-17+ cells in joints; C, CD4+INFγ+ cells in LN; D, CD4+INFγ+ cells in joints. **, P < 0.01. Data are representative of two experiments. Error bars show SEM.
Mentions: Anti-TNFα treatment of established arthritis reduced total numbers of CD4+IFNγ+ and CD4+IL-17+ cells in joints by 63% and 67%, respectively, despite being present in increased numbers in inguinal LN (Fig. 5). It was concluded that one of the mechanisms of action of anti-TNFα therapy is to inhibit immigration of pathogenic T cells to the joint or prevent their emigration from LN. It was beyond the scope of the present study to investigate the mechanisms by which anti-TNFα prevents T cell accumulation in the joint, but they are likely to include reduced chemokine and adhesion molecule expression in the joint, as has been proposed for human RA (16, 17).

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