Factor VIII tolerance: is more better?

Comment on Hausl et al, page 3415

Immune tolerance protocols have been used to eliminate factor VIII inhibitors for more than 20 years, but the mechanism for tolerance induction is not well understood. Hausl and colleagues provide mechanistic insights in this issue of Blood.

Inhibitor antibodies to factor VIII complicate the treatment of hemophilia A in about 20% of patients with severe disease. Optimal management of inhibitors consists of their elimination to permit unfettered replacement therapy with factor VIII. The strategy for elimination of inhibitor antibodies traditionally has been to administer factor VIII for prolonged periods of time with the goal of deleting reactive B-cell clones or inducing their unresponsiveness to factor VIII.

Clinicians can cite empiric examples of success with high doses of factor VIII (the “Bonn protocol”)¹  or lower doses of factor VIII to induce tolerance.²  Since factor VIII is expensive and most immune tolerance induction protocols require indwelling catheters (with the attendant risk for infection), insights into how best to achieve tolerance in as little time as possible are particularly valuable.

In this issue, Hausl and colleagues present the results of their investigation of the mechanism for immune tolerance induction in mice. They first immunized hemophilia A knock-out mice with factor VIII and transferred memory B cells to naive mice. They then showed that a single high dose of intravenous factor VIII delivered to the recipients prevented restimulation and differentiation of specific memory B cells into antibody-secreting plasma cells. Conversely, low doses of factor VIII actually stimulated antibody production.

In vitro experiments in this report indicated that the effect involved activation of caspases and Fas/Fas ligand interaction, and did not involve factor VIII–specific T cells. The “threshold” effect observed in vivo suggests that higher doses of factor VIII may be more effective than lower doses for immune tolerance induction and may lead to apoptosis of memory B cells.

It is always appropriate to be cautious when extrapolating from animal models to human diseases or conditions. For instance, the effect might be less clear in humans with hemophilia due to different response of outbred human populations compared with inbred mice (such as the B6 strain that is less responsive to factor VIII than other strains).³  Further, the in vivo experiments were done in mice lacking antibodies to factor VIII that presumably would, if present, neutralize some of the administered factor VIII.

Regardless of these limitations, this study provides mechanistic support for the high-dose strategy of immune tolerance induction. The doses of factor VIII that were most effective in inducing tolerance in this study corresponded to 200 to 2000 times normal factor VIII levels. Theoretically, a short course of a few extremely high doses of factor VIII might have practical advantages over longer duration regiments. However, this approach might pose its own risk, since chronically elevated levels of various coagulation factors (including factor VIII) are associated with higher risk for thrombosis. In all, this study suggests mechanistic explanations for clinical observations and deserves consideration in the design and interpretation of factor VIII tolerance induction trials.