Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1 in juvenile diabetes
Ciriana Orabona, Giada Mondanelli, Maria T. Pallotta, Agostinho Carvalho, Elisa Albini, Francesca Fallarino, Carmine Vacca, Claudia Volpi, Maria L. Belladonna, Maria G. Berioli, Giulia Ceccarini, Susanna M.R. Esposito, Raffaella Scattoni, Alberto Verrotti, Alessandra Ferretti, Giovanni De Giorgi, Sonia Toni, Marco Cappa, Maria C. Matteoli, Roberta Bianchi, Davide Matino, Alberta Iacono, Matteo Puccetti, Cristina Cunha, Silvio Bicciato, Cinzia Antognelli, Vincenzo N. Talesa, Lucienne Chatenoud, Dietmar Fuchs, Luc Pilotte, Benoît Van den Eynde, Manuel C. Lemos, Luigina Romani, Paolo Puccetti, Ursula Grohmann
Ciriana Orabona, Giada Mondanelli, Maria T. Pallotta, Agostinho Carvalho, Elisa Albini, Francesca Fallarino, Carmine Vacca, Claudia Volpi, Maria L. Belladonna, Maria G. Berioli, Giulia Ceccarini, Susanna M.R. Esposito, Raffaella Scattoni, Alberto Verrotti, Alessandra Ferretti, Giovanni De Giorgi, Sonia Toni, Marco Cappa, Maria C. Matteoli, Roberta Bianchi, Davide Matino, Alberta Iacono, Matteo Puccetti, Cristina Cunha, Silvio Bicciato, Cinzia Antognelli, Vincenzo N. Talesa, Lucienne Chatenoud, Dietmar Fuchs, Luc Pilotte, Benoît Van den Eynde, Manuel C. Lemos, Luigina Romani, Paolo Puccetti, Ursula Grohmann
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Research Article Immunology

Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1 in juvenile diabetes

Abstract

A defect in indoleamine 2,3-dioxygenase 1 (IDO1), which is responsible for immunoregulatory tryptophan catabolism, impairs development of immune tolerance to autoantigens in NOD mice, a model for human autoimmune type 1 diabetes (T1D). Whether IDO1 function is also defective in T1D is still unknown. We investigated IDO1 function in sera and peripheral blood mononuclear cells (PBMCs) from children with T1D and matched controls. These children were further included in a discovery study to identify SNPs in IDO1 that might modify the risk of T1D. T1D in children was characterized by a remarkable defect in IDO1 function. A common haplotype, associated with dysfunctional IDO1, increased the risk of developing T1D in the discovery and also confirmation studies. In T1D patients sharing such a common IDO1 haplotype, incubation of PBMCs in vitro with tocilizumab (TCZ) — an IL-6 receptor blocker — would, however, rescue IDO1 activity. In an experimental setting with diabetic NOD mice, TCZ was found to restore normoglycemia via IDO1-dependent mechanisms. Thus, functional SNPs of IDO1 are associated with defective tryptophan catabolism in human T1D, and maneuvers aimed at restoring IDO1 function would be therapeutically effective in at least a subgroup of T1D pediatric patients.

Authors

Ciriana Orabona, Giada Mondanelli, Maria T. Pallotta, Agostinho Carvalho, Elisa Albini, Francesca Fallarino, Carmine Vacca, Claudia Volpi, Maria L. Belladonna, Maria G. Berioli, Giulia Ceccarini, Susanna M.R. Esposito, Raffaella Scattoni, Alberto Verrotti, Alessandra Ferretti, Giovanni De Giorgi, Sonia Toni, Marco Cappa, Maria C. Matteoli, Roberta Bianchi, Davide Matino, Alberta Iacono, Matteo Puccetti, Cristina Cunha, Silvio Bicciato, Cinzia Antognelli, Vincenzo N. Talesa, Lucienne Chatenoud, Dietmar Fuchs, Luc Pilotte, Benoît Van den Eynde, Manuel C. Lemos, Luigina Romani, Paolo Puccetti, Ursula Grohmann

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Figure 3

Peripheral blood mononuclear cells (PBMCs) from T1D patients express abnormal levels of SOCS3 and IL-6R.

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Peripheral blood mononuclear cells (PBMCs) from T1D patients express abn...
(A) Absolute expression levels of SOCS3, IL6, and IL6R transcripts in untreated PBMCs normalized to ACTB expression (n = 26–97). (B) Real-time PCR analysis of SOCS3, IL6, and IL6R transcripts in PBMCs treated as in Figure 1A. Data were normalized to expression of ACTB (encoding β-actin) and presented relative to results in untreated cells (dotted line, 1-fold; n = 23–98). (C) Linear regression analyses of SOCS3, IL6, and IL6R expression vs. disease duration in T1D PBMCs stimulated with IFN-γ at 1,000 U/ml (n = 22). (D) IL-6 protein levels measured by ELISA in culture supernatants of PBMCs from control or T1D subjects either untreated or stimulated with IFN-γ (1,000 U/ml) for 48 hours (n = 15–22). (E) Immunoblot analysis of IL-6R, SOCS3, and β-tubulin in lysates of PBMCs, either unstimulated (0) or stimulated for 48 hours with IFN-γ at 1,000 U/ml, from 1 representative control subject and 1 T1D patient (indicated at the right side). (F) IL-6R/β-tubulin and SOCS3/β-tubulin ratios of scanning densitometry data obtained from immunoblot analyses as in E (all groups, n = 27). Ctrl, nondiabetic subjects. T1D, diabetic patients. Data (mean ± SEM) are the results of 4 independent measurements performed in triplicates. Data in panels A, B, D, and F were analyzed by 2-way ANOVA, followed by post hoc Bonferroni’s test. *P < 0.05; **P < 0.01.