A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice

doi:10.1084/jem.20030633

Published online 30 June 2003 doi:10.1084/jem.20030633

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© Rockefeller University Press, 0022-1007/2003/7/153 $5.00
The Journal of Experimental Medicine, Volume 198, Number 1, 153-160

A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice

Ursula Grohmann, Francesca Fallarino, Roberta Bianchi, Ciriana Orabona, Carmine Vacca, Maria C. Fioretti and 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: ugrohmann{at}tin.it

The predisposition of nonobese diabetic (NOD) mice to developautoimmunity reflects deficiencies in both peripheral and centraltolerance. Several defects have been described in these mice,among which aberrant antigen-presenting cell function and peroxynitriteformation. Prediabetes and diabetes in NOD mice have been targetedwith different outcomes by a variety of immunotherapies, includinginterferon (IFN)- ${gamma}$ . This cytokine may be instrumental in specificforms of tolerance by virtue of its ability to activate immunosuppressivetryptophan catabolism. Here, we provide evidence that IFN- ${gamma}$ failsto induce tolerizing properties in dendritic cells from highlysusceptible female mice early in prediabetes. This effect isassociated with impaired tryptophan catabolism, is related totransient blockade of the Stat1 pathway of intracellular signalingby IFN- ${gamma}$ , and is caused by peroxynitrite production. However,the use of a peroxynitrite inhibitor can rescue tryptophan catabolismand tolerance in those mice. This is the first report of anexperimental autoimmune disease in which defective toleranceis causally linked to impaired tryptophan catabolism.

Key Words: autoimmunity • indoleamine 2,3-dioxygenase • dendritic cells • tolerance • NOD mice

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