Induction of heme oxygenase-1 in factor VIII-deficient mice reduces the immune response to therapeutic factor VIII.
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.
Dimitrov
Jordan D
JD
Inserm, Unite 872, Centre de recherche des Cordeliers, Paris, France.
Dasgupta
Suryasarathi
S
Navarrete
Ana-Maria
AM
Delignat
Sandrine
S
Repesse
Yohann
Y
Meslier
Yann
Y
Planchais
Cyril
C
Teyssandier
Maud
M
Motterlini
Roberto
R
Bayry
Jagadeesh
J
Kaveri
Srinivas V
SV
Lacroix-Desmazes
Sébastien
S
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D004334:Drug Administration Schedule; D005169:Factor VIII / Q000276:immunology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006427:Hemin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000276:immunology; D007249:Inflammation; D007518:Isoantibodies / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D013997:Time Factors
D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007518:Isoantibodies; D008565:Membrane Proteins; D008665:Metalloporphyrins; C055421:tin mesoporphyrin; D006427:Hemin; C078147:F8 protein, human; D005169:Factor VIII; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse