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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7 July 2003
Article|
June 30 2003
A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice
Ursula Grohmann,
Ursula Grohmann
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Francesca Fallarino,
Francesca Fallarino
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Roberta Bianchi,
Roberta Bianchi
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Ciriana Orabona,
Ciriana Orabona
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Carmine Vacca,
Carmine Vacca
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Maria C. Fioretti,
Maria C. Fioretti
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Paolo Puccetti
Paolo Puccetti
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
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Ursula Grohmann
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Francesca Fallarino
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Roberta Bianchi
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Ciriana Orabona
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Carmine Vacca
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Maria C. Fioretti
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Paolo Puccetti
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
Address correspondence to Ursula Grohmann, Section of Pharmacology, Dept. of Experimental Medicine, University of Perugia, 06126 Perugia, Italy. Phone: 39-075-585-7460; Fax: 39-075-585-7473; E-mail: [email protected]
*
Abbreviations used in this paper: GED, guanidinoethyl disulphide; IDO, indoleamine 2,3-dioxygenase; 1-MT, 1-methyl-dl-tryptophan; NF, nuclear factor; NO, nitric oxide; NOD, nonobese diabetic.
Received:
April 17 2003
Revision Received:
May 09 2003
Accepted:
May 09 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (1): 153–160.
Article history
Received:
April 17 2003
Revision Received:
May 09 2003
Accepted:
May 09 2003
Citation
Ursula Grohmann, Francesca Fallarino, Roberta Bianchi, Ciriana Orabona, Carmine Vacca, Maria C. Fioretti, Paolo Puccetti; A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice . J Exp Med 7 July 2003; 198 (1): 153–160. doi: https://doi.org/10.1084/jem.20030633
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