tin-mesoporphyrin and Hemophilia-A

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.

Topics: Animals; Antigen-Presenting Cells; Drug Administration Schedule; Factor VIII; Gene Expression Regulation; Heme Oxygenase-1; Hemin; Hemophilia A; Histocompatibility Antigens Class II; Humans; Immunoglobulin G; Inflammation; Isoantibodies; Male; Membrane Proteins; Metalloporphyrins; Mice; Mice, Knockout; Spleen; T-Lymphocytes, Regulatory; Time Factors