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: Davide Matino, Marco Gargaro, Elena Santagostino, Matteo N D Di Minno, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Maria E Mancuso, Giovanni Di Minno, Antonio Coppola, Vincenzo N Talesa, Claudia Volpi, Carmine Vacca, Ciriana Orabona, Rossana Iannitti, Maria G Mazzucconi, Cristina Santoro, Antonella 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 10 Pg. 3766-81 (Oct 01 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 26426076 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• CPG-oligonucleotide
• Cytokines
• IDO1 protein, human
• IDO1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Isoantibodies
• NF-kappa B
• Oligodeoxyribonucleotides
• TLR9 protein, human
• Tlr9 protein, mouse
• Toll-Like Receptor 9
• F8 protein, human
• Tryptophan
• Factor VIII

Topics

• Animals
• Case-Control Studies
• Cytokines (blood)
• Dendritic Cells (enzymology)
• Drug Administration Schedule
• Enzyme Induction (drug effects)
• Factor VIII (immunology, therapeutic use)
• Hemophilia A (drug therapy, immunology)
• Humans
• Immune Tolerance
• Indoleamine-Pyrrole 2,3,-Dioxygenase (blood, physiology)
• Isoantibodies (biosynthesis, immunology)
• Leukocytes, Mononuclear (enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• Molecular Targeted Therapy
• NF-kappa B (metabolism)
• Oligodeoxyribonucleotides (administration & dosage, therapeutic use)
• Plasma Cells (immunology)
• T-Lymphocytes, Regulatory (enzymology, immunology)
• Toll-Like Receptor 9 (agonists, physiology)
• Tryptophan (metabolism)