IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII

J Clin Invest. 2015 Oct 1;125(10):3766-81. doi: 10.1172/JCI81859. Epub 2015 Aug 31.

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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • CPG-oligonucleotide
  • Cytokines
  • IDO1 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Isoantibodies
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • TLR9 protein, human
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • indoleamine 2,3-dioxygenase 1, human
  • F8 protein, human
  • Tryptophan
  • Factor VIII