title: A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice.
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.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy. ugrohmann@tin.it
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Maria C
authors.initials: MC
authors.lastname: Fioretti
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity; D004268:DNA-Binding Proteins / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D009569:Nitric Oxide / Q000502:physiology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D006146:Guanidines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; C014363:bis(2-guanidinoethyl)disulfide; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase