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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1324-1329
Prevention and treatment of factor VIII inhibitors in murine
hemophilia A
Jiahua Qian,
Mary Collins,
Arlene H. Sharpe, and
Leon W. Hoyer
From the Holland Laboratory, American Red Cross, Rockville, MD; the
Genetics Institute, Cambridge, MA; Brigham and Women's Hospital,
Harvard Medical School, Harvard University, Boston, MA; and the
Department of Medicine, George Washington University School of Medicine
and Health Sciences, Washington, DC.
Inhibitory antibody formation is a major complication of factor VIII
replacement therapy in patients with hemophilia A. To better understand
the pathogenesis of this immunologic reaction, we evaluated the role of
T-cell costimulatory signals for antifactor VIII antibody formation in
a murine model of hemophilia A. Repeated intravenous injections of
factor VIII in these factor VIII-deficient mice induced an antifactor
VIII inhibitor antibody response. This response was shown to be T-cell
dependent by its absence in hemophilic mice also deficient for the
T-cell costimulatory ligand B7-2. In separate experiments, injection of
murine CTLA4-Ig completely blocked the primary response to factor VIII
in hemophilic mice with intact B7 function. This reagent also prevented
or diminished further increases in antifactor VIII when given to
hemophilic mice with low antifactor VIII antibody titers. These studies
suggest that strategies targeting the B7-CD28 pathway are potential
therapies to prevent and treat inhibitory antifactor VIII antibodies.
Moreover, because the development of antibodies to replaced proteins
may limit the success of many human gene therapy approaches, our
results may be broadly applicable.
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