Bortezomib delays the onset of factor VIII inhibitors in experimental hemophilia A, but fails to eliminate established anti-factor VIII IgG-producing cells.

摘要

BACKGROUND: Replacement therapy with exogenous factor VIII to treat hemorrhages induces inhibitory anti-FVIII antibodies in up to 30% of patients with hemophilia A. Current approaches to eradicate FVIII inhibitors using high-dose FVIII injection protocols (immune tolerance induction) or anti-CD20 depleting antibodies (Rituximab) demonstrate limited efficacy; they are extremely expensive and/or require stringent compliance from the patients. OBJECTIVES: To investigate whether the proteasome inhibitor bortezomib, which depletes plasmocytes, modulates the anti-FVIII immune response in FVIII-deficient mice. METHODS AND RESULTS: Preventive 4-week treatment of naive mice with bortezomib at the time of FVIII administration delayed the development of inhibitory anti-FVIII IgG, and depleted plasma cells as well as different lymphoid cell subsets. Conversely, curative treatment of inhibitor-positive mice for 10 weeks, along with FVIII administration, failed to eradicate FVIII inhibitors to extents that would be clinically relevant if achieved in patients. Accordingly, bortezomib did not eradicate anti-FVIII IgG-secreting plasmocytes that had homed to survival niches in the bone marrow, despite significant elimination of total plasma cells. CONCLUSIONS: The data suggest that strategies for the efficient reduction of anti-FVIII IgG titers in patients with hemophilia A should rely on competition for survival niches for plasmocytes in the bone marrow rather than the mere use of proteasome inhibitors.