title: IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII.
abstract: The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.
authors.forename: Davide
authors.initials: D
authors.lastname: Matino
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.forename: Elena
authors.initials: E
authors.lastname: Santagostino
authors.forename: Matteo N D
authors.initials: MN
authors.lastname: Di Minno
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castaman
authors.forename: Massimo
authors.initials: M
authors.lastname: Morfini
authors.forename: Angiola
authors.initials: A
authors.lastname: Rocino
authors.forename: Maria E
authors.initials: ME
authors.lastname: Mancuso
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Minno
authors.forename: Antonio
authors.initials: A
authors.lastname: Coppola
authors.forename: Vincenzo N
authors.initials: VN
authors.lastname: Talesa
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.forename: Rossana
authors.initials: R
authors.lastname: Iannitti
authors.forename: Maria G
authors.initials: MG
authors.lastname: Mazzucconi
authors.forename: Cristina
authors.initials: C
authors.lastname: Santoro
authors.forename: Antonella
authors.initials: A
authors.lastname: Tosti
authors.forename: Sara
authors.initials: S
authors.lastname: Chiappalupi
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Sorci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tagariello
authors.forename: Donata
authors.initials: D
authors.lastname: Belvini
authors.forename: Paolo
authors.initials: P
authors.lastname: Radossi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Landolfi
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Matteo
authors.initials: M
authors.lastname: Pirro
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marchesini
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Alfonso
authors.initials: A
authors.lastname: Iorio
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000201:enzymology; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood / Q000502:physiology*; D007518:Isoantibodies / Q000096:biosynthesis* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use; D010950:Plasma Cells / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; C576710:IDO1 protein, human; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007518:Isoantibodies; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C078147:F8 protein, human; D014364:Tryptophan; D005169:Factor VIII