Induction of heme oxygenase-1 in factor VIII-deficient mice reduces the immune response to therapeutic factor VIII.

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.

• Authors: Jordan D Dimitrov, Suryasarathi Dasgupta, Ana-Maria Navarrete, Sandrine Delignat, Yohann Repesse, Yann Meslier, Cyril Planchais, Maud Teyssandier, Roberto Motterlini, Jagadeesh Bayry, Srinivas V Kaveri, Sébastien Lacroix-Desmazes
• Journal: Blood (Blood) Vol. 115 Issue 13 Pg. 2682-5 (Apr 01 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 19890094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class II
• Immunoglobulin G
• Isoantibodies
• Membrane Proteins
• Metalloporphyrins
• tin mesoporphyrin
• Hemin
• F8 protein, human
• Factor VIII
• Heme Oxygenase-1
• Hmox1 protein, mouse

Topics

• Animals
• Antigen-Presenting Cells (immunology)
• Drug Administration Schedule
• Factor VIII (immunology, therapeutic use)
• Gene Expression Regulation (drug effects)
• Heme Oxygenase-1 (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Hemin (administration & dosage, pharmacology, therapeutic use)
• Hemophilia A (drug therapy, immunology)
• Histocompatibility Antigens Class II (biosynthesis, genetics)
• Humans
• Immunoglobulin G (biosynthesis, immunology)
• Inflammation
• Isoantibodies (biosynthesis, immunology)
• Male
• Membrane Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Metalloporphyrins (pharmacology)
• Mice
• Mice, Knockout
• Spleen (immunology)
• T-Lymphocytes, Regulatory (cytology, immunology)
• Time Factors