IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII Journal Articles uri icon

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  • 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.


  • Matino, Davide
  • Gargaro, Marco
  • Santagostino, Elena
  • Di Minno, Matteo ND
  • Castaman, Giancarlo
  • Morfini, Massimo
  • Rocino, Angiola
  • Mancuso, Maria E
  • Di Minno, Giovanni
  • Coppola, Antonio
  • Talesa, Vincenzo N
  • Volpi, Claudia
  • Vacca, Carmine
  • Orabona, Ciriana
  • Iannitti, Rossana
  • Mazzucconi, Maria G
  • Santoro, Cristina
  • Tosti, Antonella
  • Chiappalupi, Sara
  • Sorci, Guglielmo
  • Tagariello, Giuseppe
  • Belvini, Donata
  • Radossi, Paolo
  • Landolfi, Raffaele
  • Fuchs, Dietmar
  • Boon, Louis
  • Pirro, Matteo
  • Marchesini, Emanuela
  • Grohmann, Ursula
  • Puccetti, Paolo
  • Iorio, Alfonso
  • Fallarino, Francesca

publication date

  • October 1, 2015

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