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A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice.

Grohmann U, Fallarino F, Bianchi R, Orabona C, Vacca C, Fioretti MC, Puccetti P - J. Exp. Med. (2003)

Bottom Line: Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-gamma.This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism.This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy. ugrohmann@tin.it

ABSTRACT
The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-gamma. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-gamma fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism.

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Ability of GED to rescue the tolerizing properties of CD8+ DCs from early prediabetic NOD female mice. Combinations of CD8− and CD8+ DCs were loaded with NRP-A7 and injected into recipient mice to be assayed at 2 wk for skin test reactivity to the eliciting peptide. CD8− DCs were used as such or after activation with IL-12, whereas CD8+ DCs were exposed to IFN-γ. Groups of CD8+ DCs were coexposed in vitro to 1-MT and/or GED before peptide loading. (*) P < 0.001, experimental versus control footpads. One experiment is reported representative of three.
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fig5: Ability of GED to rescue the tolerizing properties of CD8+ DCs from early prediabetic NOD female mice. Combinations of CD8− and CD8+ DCs were loaded with NRP-A7 and injected into recipient mice to be assayed at 2 wk for skin test reactivity to the eliciting peptide. CD8− DCs were used as such or after activation with IL-12, whereas CD8+ DCs were exposed to IFN-γ. Groups of CD8+ DCs were coexposed in vitro to 1-MT and/or GED before peptide loading. (*) P < 0.001, experimental versus control footpads. One experiment is reported representative of three.

Mentions: Because of the ability of GED to restore IFN-γ responsiveness in vitro in CD8+ DCs from 4-wk-old NOD female mice, we wanted to investigate the effect of GED on the in vivo ability of the latter cells to modulate priming to NRP-A7 by CD8− DCs. We adopted an experimental model analogous to that of Fig. 1, in which a combination of CD8− and CD8+ DCs was injected into NOD mice to be assayed at 2 wk for skin test reactivity to the eliciting peptide. DCs from 4-wk-old NOD female mice were fractionated, treated with cytokines, loaded with the peptide, and injected into recipient hosts. IL-12 was used to enhance the priming ability of CD8− DCs and IFN-γ to induce tolerizing properties in CD8+ DCs, as illustrated above. Groups of CD8+ DCs were coexposed to 1-MT and/or GED during IFN-γ activation. As expected, IFN-γ treatment alone of CD8+ DCs did not enable these cells to prevent host priming to NRP-A7 (Fig. 5). However, the copresence of GED during IFN-γ activation rescued the ability of CD8+ DCs to suppress priming. The inhibitory effect was dependent on tryptophan catabolism as it was negated by the addition of 1-MT to IFN-γ and GED. These data demonstrate a role for peroxynitrite inhibition of tryptophan catabolism in the poor tolerogenic ability of DCs from NOD female mice in early prediabetes.


A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice.

Grohmann U, Fallarino F, Bianchi R, Orabona C, Vacca C, Fioretti MC, Puccetti P - J. Exp. Med. (2003)

Ability of GED to rescue the tolerizing properties of CD8+ DCs from early prediabetic NOD female mice. Combinations of CD8− and CD8+ DCs were loaded with NRP-A7 and injected into recipient mice to be assayed at 2 wk for skin test reactivity to the eliciting peptide. CD8− DCs were used as such or after activation with IL-12, whereas CD8+ DCs were exposed to IFN-γ. Groups of CD8+ DCs were coexposed in vitro to 1-MT and/or GED before peptide loading. (*) P < 0.001, experimental versus control footpads. One experiment is reported representative of three.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196078&req=5

fig5: Ability of GED to rescue the tolerizing properties of CD8+ DCs from early prediabetic NOD female mice. Combinations of CD8− and CD8+ DCs were loaded with NRP-A7 and injected into recipient mice to be assayed at 2 wk for skin test reactivity to the eliciting peptide. CD8− DCs were used as such or after activation with IL-12, whereas CD8+ DCs were exposed to IFN-γ. Groups of CD8+ DCs were coexposed in vitro to 1-MT and/or GED before peptide loading. (*) P < 0.001, experimental versus control footpads. One experiment is reported representative of three.
Mentions: Because of the ability of GED to restore IFN-γ responsiveness in vitro in CD8+ DCs from 4-wk-old NOD female mice, we wanted to investigate the effect of GED on the in vivo ability of the latter cells to modulate priming to NRP-A7 by CD8− DCs. We adopted an experimental model analogous to that of Fig. 1, in which a combination of CD8− and CD8+ DCs was injected into NOD mice to be assayed at 2 wk for skin test reactivity to the eliciting peptide. DCs from 4-wk-old NOD female mice were fractionated, treated with cytokines, loaded with the peptide, and injected into recipient hosts. IL-12 was used to enhance the priming ability of CD8− DCs and IFN-γ to induce tolerizing properties in CD8+ DCs, as illustrated above. Groups of CD8+ DCs were coexposed to 1-MT and/or GED during IFN-γ activation. As expected, IFN-γ treatment alone of CD8+ DCs did not enable these cells to prevent host priming to NRP-A7 (Fig. 5). However, the copresence of GED during IFN-γ activation rescued the ability of CD8+ DCs to suppress priming. The inhibitory effect was dependent on tryptophan catabolism as it was negated by the addition of 1-MT to IFN-γ and GED. These data demonstrate a role for peroxynitrite inhibition of tryptophan catabolism in the poor tolerogenic ability of DCs from NOD female mice in early prediabetes.

Bottom Line: Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-gamma.This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism.This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy. ugrohmann@tin.it

ABSTRACT
The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-gamma. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-gamma fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism.

Show MeSH
Related in: MedlinePlus