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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3415-3422.
Prepublished online as a Blood First Edition Paper on August 9, 2005; DOI 10.1182/blood-2005-03-1182.
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Submitted March 23, 2005
Accepted July 15, 2005
High dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors
Christina Hausl, Rafi U Ahmad, Maria Sasgary, Christopher B Doering, Pete Lollar, Gunter Richter, Hans P Schwarz, Peter L Turecek, and Birgit M Reipert*
BMT-Research, Vienna, Austria
Baxter BioScience, Vienna, Austria
AFLAC Cancer Center and Blood Disorders Service, Children's Hospital of Atlanta, Atlanta, Georgia, USA
BMT-Research, Vienna, Austria; Baxter BioScience, Vienna, Austria
* Corresponding author; email: birgit_reipert{at}baxter.com.
Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene. About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and induce long-lasting immune tolerance. Little is known, however, about the immunological mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the re-stimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in hemophilia A patients who receive high doses of FVIII.
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