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A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice

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...

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Autores principales: Grohmann, Ursula, Fallarino, Francesca, Bianchi, Roberta, Orabona, Ciriana, Vacca, Carmine, Fioretti, Maria C., Puccetti, Paolo
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196078/
https://www.ncbi.nlm.nih.gov/pubmed/12835483
http://dx.doi.org/10.1084/jem.20030633
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author Grohmann, Ursula
Fallarino, Francesca
Bianchi, Roberta
Orabona, Ciriana
Vacca, Carmine
Fioretti, Maria C.
Puccetti, Paolo
author_facet Grohmann, Ursula
Fallarino, Francesca
Bianchi, Roberta
Orabona, Ciriana
Vacca, Carmine
Fioretti, Maria C.
Puccetti, Paolo
author_sort Grohmann, Ursula
collection PubMed
description 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)-γ. 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-γ 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-γ, 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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spelling pubmed-21960782008-04-11 A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice Grohmann, Ursula Fallarino, Francesca Bianchi, Roberta Orabona, Ciriana Vacca, Carmine Fioretti, Maria C. Puccetti, Paolo J Exp Med Article 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)-γ. 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-γ 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-γ, 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. The Rockefeller University Press 2003-07-07 /pmc/articles/PMC2196078/ /pubmed/12835483 http://dx.doi.org/10.1084/jem.20030633 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Grohmann, Ursula
Fallarino, Francesca
Bianchi, Roberta
Orabona, Ciriana
Vacca, Carmine
Fioretti, Maria C.
Puccetti, Paolo
A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
title A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
title_full A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
title_fullStr A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
title_full_unstemmed A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
title_short A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
title_sort defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196078/
https://www.ncbi.nlm.nih.gov/pubmed/12835483
http://dx.doi.org/10.1084/jem.20030633
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