Abstract
Replacement therapy with exogenous factor VIII (FVIII) to treat hemorrhages induces anti-FVIII inhibitory immunoglobulin G in up to 30% of patients with hemophilia A. Chronic inflammation associated with recurrent bleedings is a proposed risk factor for FVIII inhibitor development. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory activity. Here, we demonstrate that induction of HO-1 before FVIII administration drastically reduces the onset of the anti-FVIII humoral immune response. The protective effect was specific for HO-1 because it was reproduced on administration of the end products of HO-1 activity, carbon monoxide, and bilirubin, and prevented by the pharmacologic inhibition of HO-1 using tin mesoporphyrin IX. HO-1 induction was associated with decreased major histocompatibility complex class II expression by splenic antigen-presenting cells and reduced T-cell proliferation. Triggering the endogenous anti-inflammatory machinery before FVIII administration may represent a novel therapeutic option for preventing the development of FVIII inhibitors in hemophilia A patients.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antigen-Presenting Cells / immunology
-
Drug Administration Schedule
-
Factor VIII / immunology
-
Factor VIII / therapeutic use*
-
Gene Expression Regulation / drug effects
-
Heme Oxygenase-1 / antagonists & inhibitors
-
Heme Oxygenase-1 / biosynthesis
-
Heme Oxygenase-1 / genetics
-
Heme Oxygenase-1 / physiology*
-
Hemin / administration & dosage*
-
Hemin / pharmacology
-
Hemin / therapeutic use
-
Hemophilia A / drug therapy
-
Hemophilia A / immunology*
-
Histocompatibility Antigens Class II / biosynthesis
-
Histocompatibility Antigens Class II / genetics
-
Humans
-
Immunoglobulin G / biosynthesis*
-
Immunoglobulin G / immunology
-
Inflammation
-
Isoantibodies / biosynthesis*
-
Isoantibodies / immunology
-
Male
-
Membrane Proteins / antagonists & inhibitors
-
Membrane Proteins / biosynthesis
-
Membrane Proteins / genetics
-
Membrane Proteins / physiology*
-
Metalloporphyrins / pharmacology
-
Mice
-
Mice, Knockout
-
Spleen / immunology
-
T-Lymphocytes, Regulatory / cytology
-
T-Lymphocytes, Regulatory / immunology
-
Time Factors
Substances
-
Histocompatibility Antigens Class II
-
Immunoglobulin G
-
Isoantibodies
-
Membrane Proteins
-
Metalloporphyrins
-
tin mesoporphyrin
-
Hemin
-
F8 protein, human
-
Factor VIII
-
Heme Oxygenase-1
-
Hmox1 protein, mouse