Please use this identifier to cite or link to this item: https://hdl.handle.net/1822/58064

TitleDeficiency of immunoregulatory indoleamine 2,3-dioxygenase 1 in juvenile diabetes
Author(s)Orabona, Ciriana
Mondanelli, Giada
Pallotta, Maria T.
Carvalho, Agostinho
Albini, Elisa
Fallarino, Francesca
Vacca, Carmine
Volpi, Claudia
Belladonna, Maria L.
Cunha, Cristina
KeywordsAutoimmunity
Immunology
Amino acid metabolism
Diabetes
Immunotherapy
Issue date22-Mar-2018
PublisherAmerican Society for Clinical Investigation
JournalJCI Insight
Abstract(s)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.
TypeArticle
URIhttps://hdl.handle.net/1822/58064
DOI10.1172/jci.insight.96244
ISSN2379-3708
e-ISSN2379-3708
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em revistas internacionais / Papers in international journals

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