TY - JOUR
T1 - IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII
AU - Matino, Davide
AU - Gargaro, Marco
AU - Santagostino, Elena
AU - Di Minno, Matteo N D
AU - Castaman, Giancarlo
AU - Morfini, Massimo
AU - Rocino, Angiola
AU - Mancuso, Maria E.
AU - Di Minno, Giovanni
AU - Coppola, Antonio
AU - Talesa, Vincenzo N.
AU - Volpi, Claudia
AU - Vacca, Carmine
AU - Orabona, Ciriana
AU - Iannitti, Rossana
AU - Mazzucconi, Maria G.
AU - Santoro, Cristina
AU - Tosti, Antonella
AU - Chiappalupi, Sara
AU - Sorci, Guglielmo
AU - Tagariello, Giuseppe
AU - Belvini, Donata
AU - Radossi, Paolo
AU - Landolfi, Raffaele
AU - Fuchs, Dietmar
AU - Boon, Louis
AU - Pirro, Matteo
AU - Marchesini, Emanuela
AU - Grohmann, Ursula
AU - Puccetti, Paolo
AU - Iorio, Alfonso
AU - Fallarino, Francesca
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI81859
DO - 10.1172/JCI81859
M3 - Article
AN - SCOPUS:84943311784
VL - 125
SP - 3766
EP - 3781
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -