Dimitrov JD, Dasgupta S, Navarrete AM, Delignat S, Repesse Y, Meslier Y, Planchais C, Teyssandier M, Motterlini R, Bayry J, Kaveri SV, Lacroix-Desmazes S
Induction of heme oxygenase-1 in factor VIII-deficient mice reduces the immune response to therapeutic factor VIII. [JOURNAL ARTICLE]
Blood 2009 Nov 4.
Replacement therapy with exogenous factor VIII (FVIII) to treat hemorrhages induces anti-FVIII inhibitory IgG 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 prior to FVIII administration drastically reduces the onset of the anti-FVIII humoral immune response. The protective effect was specific for HO-1 since it was reproduced upon administration of the end products of HO-1 activity, carbon monoxide (CO) and bilirubin, and prevented by the pharmacological inhibition of HO-1 using tin mesoporphyrin IX. HO-1 induction was associated with decreased MHC 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.
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