IDO1 suppresses inhibitor development in hemophilia A treated with factor VIIIстатья из журнала
Аннотация: 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.
Год издания: 2015
Авторы: Davide Matino, Marco Gargaro, Elena Santagostino, Matteo Nicola Dario Di Minno, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Maria Elisa Mancuso, Giovanni Di Minno, Antonio Coppola, Vincenzo Nicola Talesa, Claudia Volpi, Carmine Vacca, Ciriana Orabona, Rossana G. Iannitti, Maria Gabriella Mazzucconi, Cristina Santoro, Antonellá Tosti, Sara Chiappalupi, Guglielmo Sorci, Giuseppe Tagariello, Donata Belvini, Paolo Radossi, Raffaele Landolfi, Dietmar Fuchs, Louis Boon, Matteo Pirro, Emanuela Marchesini, Ursula Grohmann, Paolo Puccetti, Alfonso Iorio, Francesca Fallarino
Издательство: American Society for Clinical Investigation
Источник: Journal of Clinical Investigation
Ключевые слова: Hemophilia Treatment and Research, Bipolar Disorder and Treatment, Adolescent and Pediatric Healthcare
Другие ссылки: Journal of Clinical Investigation (PDF)
Journal of Clinical Investigation (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)
Journal of Clinical Investigation (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)
Открытый доступ: bronze
Том: 125
Выпуск: 10
Страницы: 3766–3781